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Papers by Sandra Nijmeijer

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4... more Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and two of its hydroxylated metabolites [5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxy-methylsulfamethazine (6CH2OHSMZ)J were determined in male and female rats, in castrated males, and in rats pretreated with various steroid hormones. Male rats had a 2-fold higher SMZ plasma clear-ance than females, castrates, and males treated with flutamide (a testosterone antagonist). When castrated male rats were treated with testosterone or trenbolone, SMZ plasma clearance returned to normal values. Higher SMZ plasma clearance rates in the presence of androgens went together with higher urinary recoveries of the 6CH2OHSMZ metabolite. In hepatic microsomes of male rats lower apparent KM values, and higher values for 6CH2OHSMZ and 5OHSMZ formation were found than in microsomes of female rats. Castration or treatment of male rats with flutamide markedly reduced

Archives of Toxicology, 2020

In chemical risk assessment, default uncertainty factors are used to account for interspecies and... more In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics. Electric eel enzyme and human blood of 20 different donors (12 men/8 women) were exposed to eight different compounds (chlorpyrifos, chlorpyrifos-oxon, phosmet, phosmet-oxon, diazinon, diazinon-oxon, pirimicarb, rivastigmine) and inhibition of AChE was measured using the Ellman method. The organophosphate parent compounds, chlorpyrifos, phosmet and diazinon, did not show inhibition of AChE. All other compounds showed concentration-dependent inhibition of AChE, with IC50s in human blood ranging from 0.2–29 µM and IC20s ranging from 0...

Environmental Research, 2022

BACKGROUND Epidemiological studies have associated biomass combustion with (respiratory) morbidit... more BACKGROUND Epidemiological studies have associated biomass combustion with (respiratory) morbidity and mortality, primarily in indoor settings. Barbecuing results in high outdoor air pollution exposures, but the health effects are unknown. OBJECTIVE The objective was to investigate short-term changes in respiratory health in healthy adults, associated with exposure to barbecue fumes. METHODS 16 healthy, adult volunteers were exposed to barbecue smoke in outdoor air in rest during 1.5 hours, using a repeated-measures design. Major air pollutants were monitored on-site, including particulate matter <2.5 μm (PM2.5), particle number concentrations (PNC) and black- and brown carbon. At the same place and time-of-day, subjects participated in a control session, during which they were not exposed to barbecue smoke. Before and immediately after all sessions lung function was measured. Before, immediately after, 4- and 18 hours post-sessions nasal expression levels of interleukin (IL)-8, IL6 and Tumor Necrosis Factor alpha (TNFα) were determined in nasal swabs, using quantitative polymerase chain reaction. Associations between major air pollutants, lung function and inflammatory markers were assessed using mixed linear regression models. RESULTS High PM2.5 levels and PNCs were observed during barbecue sessions, with averages ranging from 553-1062 μg/m3 and 109,000-463,000 pt/cm3, respectively. Average black- and brown carbon levels ranged between 4.1-13.0 and 5.0-16.2 μg/m3. A 1000 μg/m3 increase in PM2.5 was associated with 2.37 (0.97, 4.67) and 2.21 (0.98, 5.00) times higher expression of IL8, immediately- and 18 hours after exposure. No associations were found between air pollutants and lung function, or the expression of IL6 or TNFα. DISCUSSION Short-term exposure to air pollutants emitted from barbecuing was associated with a mild respiratory response in healthy young adults, including prolonged increase in nasal IL8 without a change in lung function and other measured inflammatory markers. The results might indicate prolonged respiratory inflammation, due to short-term exposure to barbecue fumes.

Antimicrobial Agents and Chemotherapy, 1996

Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has be... more Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 and 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, and P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin and substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex format...

Drug metabolism and disposition: the biological fate of chemicals, 1995

Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been... more Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds that are simultaneously administered. To explain this, it has been suggested that tiamulin selectively inhibits oxidative drug metabolism via the formation of a cytochrome P450 metabolic intermediate complex. The aim of the present study was to provide further support for this hypothesis. When hepatic microsomes and cultured primary pig hepatocytes were incubated with tiamulin, a maximum in the absorbance spectrum at 455 nm was observed, which disappeared after adding KFe(CN)6. When hepatocytes were incubated with tiamulin for 72 hr, cytochrome P450 content and cytochrome P4503A apoprotein levels were increased. Tiamulin strongly inhibited and concentration dependently inhibited the hydroxylation rate of testosterone at the 6 beta-position in both microsomes and hepatocytes, and the microsomal N-demet...

American journal of veterinary research, 1988

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg... more Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to...

American journal of veterinary research, 1992

The influence of infection with Ehrlichia phagocytophila (EP) on serum thyroid hormone concentrat... more The influence of infection with Ehrlichia phagocytophila (EP) on serum thyroid hormone concentrations and on antipyrine (25 mg/kg of body weight, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. Mean thyroid hormone concentrations moderately decreased in EP-infected goats, with maximal decrease in total and free triiodothyronine and thyroxine serum concentrations of 56, 64, 23, and 19%, respectively. The estimated pharmacokinetic values of antipyrine (AP) in EP-infected goats were similar to those in the goats when healthy. However, glucuronidation of the AP-metabolites 3-hydroxymethyl-AP, 4,4'-dihydroxy-AP, and 4-hydroxy-AP was reduced during the febrile episode of the acute-phase response to EP infection.

American journal of veterinary research, 1992

The influence of triiodothyronine (5 micrograms/kg of body weight, sc, q 12 h for 7 days) on anti... more The influence of triiodothyronine (5 micrograms/kg of body weight, sc, q 12 h for 7 days) on antipyrine (AP, 25 mg/kg, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. After triiodothyronine treatment, a significant increase in AP elimination was found. However, the observed changes in clearances for production of AP metabolites (nor-AP, 3-hydroxymethyl-AP; 4-hydroxy-AP, and 4,4'-dihydroxy-AP) do not suggest a clear selectivity of triiodothyronine toward any of the metabolic pathways of AP.

Xenobiotica, 1991

1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both... more 1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both sexes of four animal species: rat, dwarf goat, rabbit and cattle. 2. No sex differences in plasma elimination of antipyrine were found in rabbit and goat; however, in rat and cattle the effect of sex was marked. As expected, male rat showed a higher plasma clearance value than female. In contrast bulls showed a significantly lower clearance value than cows. 3. Metabolite patterns varied widely from one species to another. The major urinary metabolite in rabbit and the two ruminant species was 4-hydroxy-antipyrine (OHA), whereas in rat 3-hydroxymethylantipyrine (HMA) was quantitatively the most important metabolite. 4. HMA was excreted in the 24 h urine in larger amounts by male rats than by females. Metabolism of antipyrine to HMA was also sexually different in the dwarf goat, but in this species females were more active than males. The effect of sex on the metabolite pattern in cattle was marked. 5. It is concluded that in ruminants there may be xenobiotic metabolic pathways which are under hormonal control, just as there are in rats and mice. If hormones influence drug metabolism in food-producing animals, residue levels of xenobiotics or their metabolites in food from animal origin may differ with the sex of the animal, or may be altered after treatment with anabolic hormones.

Toxicology and Applied Pharmacology, 2013

Toxicological Sciences, 2006

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been in use as a... more Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been in use as additives in various consumer products. Structural similarities of PBDEs with other polyhalogenated aromatic hydrocarbons that show affinity for the aryl hydrocarbon receptor (AhR), such as some polychlorinated biphenyls, raised concerns about their possible dioxin-like properties. We studied the ability of environmentally relevant PBDEs (BDE-47,-99,-100,-153,-154, and-183) and the "planar" congener BDE-77 to bind and/or activate the AhR in stably transfected rodent hepatoma cell lines with an AhR-responsive enhanced green fluorescent protein (AhR-EGFP) reporter gene (H1G1.1c3 mouse and H4G1.1c2 rat hepatoma). 7-Ethoxyresorufin-Odee-thylation (EROD) was used as a marker for CYP1A1 activity. Dose-and bromination-specific inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced responses was measured by their ability to inhibit the induction of AhR-EGFP expression and EROD activity. Individual exposure to these PBDEs did not result in any increase in induction of AhR-EGFP or CYP1A1 activity. The lower brominated PBDEs showed the strongest inhibitory effect on TCDD-induced activities in both cell lines. While the highest brominated PBDE tested, BDE-183, inhibited EROD activity, it did not affect the induction of AhR-EGFP expression. Similar findings were observed after exposing stably transfected human hepatoma (xenobiotic response element [XRE]-HepG2) cells to these PBDEs, resulting in a small but statically significant agonistic effect on XRE-driven luciferase activity. Co-exposure with TCDD resulted again in antagonistic effects, confirming that the inhibitory effect of these PBDEs on TCDD-induced responses was not only due to direct interaction at receptor level but also at DNA-binding level. This antagonism was confirmed for BDE-99 in HepG2 cells transiently transfected with a Gal4-AhR construct and the corresponding Gal4-Luc reporter gene. In addition, a chromatin immunoprecipitation assay further confirmed that BDE-99 could bind to the AhR and activate the AhR nuclear translocation and dioxin responsive element (DRE) binding in the context of the CYP1A1 promoter. However, the transactivation function of the BDE-99-activated AhR seems to be very weak. These combined results suggest that PBDEs do bind but not activate the AhR-AhR nuclear translocator protein-XRE complex.

Research in Veterinary Science, 1993

Journal of Veterinary Pharmacology and Therapeutics, 1996

Journal of Veterinary Pharmacology and Therapeutics, 1993

regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatme... more regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatment on plasma disposition and metabolite formation of sulphadimidine. J. vet. Pharma-601. Therap. 16, 55-62. Sulphadimidine (20 mg/kg i.v.) plasma elimination and metabolite formation were studied in intact male, castrated male, and female dwarf goats. Plasma pharmacokinetics and urinary metabolite patterns were first studied in untreated animals. Afterwards, females and castrates were treated with a combination of testosterone-propionate (1 mg/kg) and 17P-oestradiolbenzoate (0.02 mg/kg) once every 3 days, for a period of 4 weeks. In untreated animals, males showed a considerably lower plasma clearance than females or castrates. This was accompanied by lower partial clearances for the production of two hydroxylated sulphadimidine metabolites. After hormonal treatment of females and castrates, sulphadimidine plasma clearance was significantly reduced, to values corresponding with those observed in control males. Furthermore, hydroxylation was significantly inhibited after treatment. The results indicate that sulphadimidine hydroxylation in the goat is performed by enzymes of the cytochrome P450 complex which are strongly influenced by gonadal hormones. Androgens seem to play a central role in this respect.

Journal of Veterinary Pharmacology and Therapeutics, 1993

Effect of gonadal hormones o n the plasma clearanw and nietaliolite forniation of antipyrine in t... more Effect of gonadal hormones o n the plasma clearanw and nietaliolite forniation of antipyrine in the dwarf goat. ,I. vct. Pltnrmacol. T/LUU#I. 'I'he effect of' gonadal liornwies on the plasma elimination and urinary metabolite profile o f antipyrine was studied in tlwaif goats. Fernale goats were treated with testosterone a n d male goats were treated with 17fi-oestradiol. tr-atecl males were treated witti either testosterone or 17fi-oesti~atliol. Antipyrine (25 mglkg, i.v.) was given both hefore a n d after the 1ioi.inon;il treatments. T h e effects of the hormonal status on the plasma elimination of' the parent compound were not consistent. This was possibly due t o the fact that formation of' the main nietabolite of antipyrine in the goat, 4-hytltoxy aritipyrine (OHA), w;is not affected b y sex or hormonal treatnient. O n tlie other hand, there were clear effects of' hormonal status on urinary excr-etion of the t h w e other metat)olites. In females a n d castrated males testosterone suppressed tlie formation of' norantipyrine (NOKA), 3-hydroxymethylantipyrine (HMA) a n d 4,4'-dihydroxyantipyrine (DOHA). Intact males produced smaller amounts o f these rrietabolites than females. I t is concluded that distinct xenobiotic nietaholir.ing p t h w a y s exist in the dwarf' goat, which a r e influenced in their activity b y gonadal Iiorniones. This confirms previous findings in rats and mice. T h e possibility that sex hormones influence d r u g metabolisrn in fiiod-t)ro(lucing animals could have consequences for veterinary therapeutics a n d public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic d r u g nietabolism, it is very important t o include the determination of metabolites.

Journal of Veterinary Pharmacology and Therapeutics, 1989

Journal of Veterinary Pharmacology and Therapeutics, 1988

Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4... more Plasma disposition and urinary recovery of sulfamethazine (SMZ), its N4-acetylated metabolite (N4AcSMZ), and two of its hydroxylated metabolites [5-hydroxysulfamethazine (5OHSMZ) and 6-hydroxy-methylsulfamethazine (6CH2OHSMZ)J were determined in male and female rats, in castrated males, and in rats pretreated with various steroid hormones. Male rats had a 2-fold higher SMZ plasma clear-ance than females, castrates, and males treated with flutamide (a testosterone antagonist). When castrated male rats were treated with testosterone or trenbolone, SMZ plasma clearance returned to normal values. Higher SMZ plasma clearance rates in the presence of androgens went together with higher urinary recoveries of the 6CH2OHSMZ metabolite. In hepatic microsomes of male rats lower apparent KM values, and higher values for 6CH2OHSMZ and 5OHSMZ formation were found than in microsomes of female rats. Castration or treatment of male rats with flutamide markedly reduced

Archives of Toxicology, 2020

In chemical risk assessment, default uncertainty factors are used to account for interspecies and... more In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics. Electric eel enzyme and human blood of 20 different donors (12 men/8 women) were exposed to eight different compounds (chlorpyrifos, chlorpyrifos-oxon, phosmet, phosmet-oxon, diazinon, diazinon-oxon, pirimicarb, rivastigmine) and inhibition of AChE was measured using the Ellman method. The organophosphate parent compounds, chlorpyrifos, phosmet and diazinon, did not show inhibition of AChE. All other compounds showed concentration-dependent inhibition of AChE, with IC50s in human blood ranging from 0.2–29 µM and IC20s ranging from 0...

Environmental Research, 2022

BACKGROUND Epidemiological studies have associated biomass combustion with (respiratory) morbidit... more BACKGROUND Epidemiological studies have associated biomass combustion with (respiratory) morbidity and mortality, primarily in indoor settings. Barbecuing results in high outdoor air pollution exposures, but the health effects are unknown. OBJECTIVE The objective was to investigate short-term changes in respiratory health in healthy adults, associated with exposure to barbecue fumes. METHODS 16 healthy, adult volunteers were exposed to barbecue smoke in outdoor air in rest during 1.5 hours, using a repeated-measures design. Major air pollutants were monitored on-site, including particulate matter <2.5 μm (PM2.5), particle number concentrations (PNC) and black- and brown carbon. At the same place and time-of-day, subjects participated in a control session, during which they were not exposed to barbecue smoke. Before and immediately after all sessions lung function was measured. Before, immediately after, 4- and 18 hours post-sessions nasal expression levels of interleukin (IL)-8, IL6 and Tumor Necrosis Factor alpha (TNFα) were determined in nasal swabs, using quantitative polymerase chain reaction. Associations between major air pollutants, lung function and inflammatory markers were assessed using mixed linear regression models. RESULTS High PM2.5 levels and PNCs were observed during barbecue sessions, with averages ranging from 553-1062 μg/m3 and 109,000-463,000 pt/cm3, respectively. Average black- and brown carbon levels ranged between 4.1-13.0 and 5.0-16.2 μg/m3. A 1000 μg/m3 increase in PM2.5 was associated with 2.37 (0.97, 4.67) and 2.21 (0.98, 5.00) times higher expression of IL8, immediately- and 18 hours after exposure. No associations were found between air pollutants and lung function, or the expression of IL6 or TNFα. DISCUSSION Short-term exposure to air pollutants emitted from barbecuing was associated with a mild respiratory response in healthy young adults, including prolonged increase in nasal IL8 without a change in lung function and other measured inflammatory markers. The results might indicate prolonged respiratory inflammation, due to short-term exposure to barbecue fumes.

Antimicrobial Agents and Chemotherapy, 1996

Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has be... more Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 and 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, and P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin and substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex format...

Drug metabolism and disposition: the biological fate of chemicals, 1995

Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been... more Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds that are simultaneously administered. To explain this, it has been suggested that tiamulin selectively inhibits oxidative drug metabolism via the formation of a cytochrome P450 metabolic intermediate complex. The aim of the present study was to provide further support for this hypothesis. When hepatic microsomes and cultured primary pig hepatocytes were incubated with tiamulin, a maximum in the absorbance spectrum at 455 nm was observed, which disappeared after adding KFe(CN)6. When hepatocytes were incubated with tiamulin for 72 hr, cytochrome P450 content and cytochrome P4503A apoprotein levels were increased. Tiamulin strongly inhibited and concentration dependently inhibited the hydroxylation rate of testosterone at the 6 beta-position in both microsomes and hepatocytes, and the microsomal N-demet...

American journal of veterinary research, 1988

Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg... more Plasma elimination rates of sulfamethazine (100 mg/kg of body weight, IV), trimethoprim (20 mg/kg, IV), and antipyrine (35 mg/kg, IV) were studied in adult female dwarf goats (n = 5) before and after implantation with trenbolone acetate (5 mg/kg). Pretreatment with trenbolone caused a significant decrease in the elimination rate of the drugs tested: for sulfamethazine, 5 times; for antipyrine, 3 times; and for trimethoprim, 2 times. After treatment with testosterone (1 mg/kg, SC, twice weekly for 2.5 weeks), female goats (n = 5) had a similar decrease in the elimination rate of sulfamethazine. Other induced effects included a change in social behavior, a lower voice, and the development of a typical billy goat-like odor. Plasma creatinine concentrations after androgen administration were significantly higher than those before androgen administration; changes were not observed in plasma urea values. Because of the differences observed, we believe that more attention should be paid to...

American journal of veterinary research, 1992

The influence of infection with Ehrlichia phagocytophila (EP) on serum thyroid hormone concentrat... more The influence of infection with Ehrlichia phagocytophila (EP) on serum thyroid hormone concentrations and on antipyrine (25 mg/kg of body weight, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. Mean thyroid hormone concentrations moderately decreased in EP-infected goats, with maximal decrease in total and free triiodothyronine and thyroxine serum concentrations of 56, 64, 23, and 19%, respectively. The estimated pharmacokinetic values of antipyrine (AP) in EP-infected goats were similar to those in the goats when healthy. However, glucuronidation of the AP-metabolites 3-hydroxymethyl-AP, 4,4'-dihydroxy-AP, and 4-hydroxy-AP was reduced during the febrile episode of the acute-phase response to EP infection.

American journal of veterinary research, 1992

The influence of triiodothyronine (5 micrograms/kg of body weight, sc, q 12 h for 7 days) on anti... more The influence of triiodothyronine (5 micrograms/kg of body weight, sc, q 12 h for 7 days) on antipyrine (AP, 25 mg/kg, IV) plasma elimination and urinary metabolite excretion was studied in castrated male dwarf goats. After triiodothyronine treatment, a significant increase in AP elimination was found. However, the observed changes in clearances for production of AP metabolites (nor-AP, 3-hydroxymethyl-AP; 4-hydroxy-AP, and 4,4'-dihydroxy-AP) do not suggest a clear selectivity of triiodothyronine toward any of the metabolic pathways of AP.

Xenobiotica, 1991

1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both... more 1. The plasma disposition of antipyrine, and its urinary metabolite pattern, were studied in both sexes of four animal species: rat, dwarf goat, rabbit and cattle. 2. No sex differences in plasma elimination of antipyrine were found in rabbit and goat; however, in rat and cattle the effect of sex was marked. As expected, male rat showed a higher plasma clearance value than female. In contrast bulls showed a significantly lower clearance value than cows. 3. Metabolite patterns varied widely from one species to another. The major urinary metabolite in rabbit and the two ruminant species was 4-hydroxy-antipyrine (OHA), whereas in rat 3-hydroxymethylantipyrine (HMA) was quantitatively the most important metabolite. 4. HMA was excreted in the 24 h urine in larger amounts by male rats than by females. Metabolism of antipyrine to HMA was also sexually different in the dwarf goat, but in this species females were more active than males. The effect of sex on the metabolite pattern in cattle was marked. 5. It is concluded that in ruminants there may be xenobiotic metabolic pathways which are under hormonal control, just as there are in rats and mice. If hormones influence drug metabolism in food-producing animals, residue levels of xenobiotics or their metabolites in food from animal origin may differ with the sex of the animal, or may be altered after treatment with anabolic hormones.

Toxicology and Applied Pharmacology, 2013

Toxicological Sciences, 2006

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been in use as a... more Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been in use as additives in various consumer products. Structural similarities of PBDEs with other polyhalogenated aromatic hydrocarbons that show affinity for the aryl hydrocarbon receptor (AhR), such as some polychlorinated biphenyls, raised concerns about their possible dioxin-like properties. We studied the ability of environmentally relevant PBDEs (BDE-47,-99,-100,-153,-154, and-183) and the "planar" congener BDE-77 to bind and/or activate the AhR in stably transfected rodent hepatoma cell lines with an AhR-responsive enhanced green fluorescent protein (AhR-EGFP) reporter gene (H1G1.1c3 mouse and H4G1.1c2 rat hepatoma). 7-Ethoxyresorufin-Odee-thylation (EROD) was used as a marker for CYP1A1 activity. Dose-and bromination-specific inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced responses was measured by their ability to inhibit the induction of AhR-EGFP expression and EROD activity. Individual exposure to these PBDEs did not result in any increase in induction of AhR-EGFP or CYP1A1 activity. The lower brominated PBDEs showed the strongest inhibitory effect on TCDD-induced activities in both cell lines. While the highest brominated PBDE tested, BDE-183, inhibited EROD activity, it did not affect the induction of AhR-EGFP expression. Similar findings were observed after exposing stably transfected human hepatoma (xenobiotic response element [XRE]-HepG2) cells to these PBDEs, resulting in a small but statically significant agonistic effect on XRE-driven luciferase activity. Co-exposure with TCDD resulted again in antagonistic effects, confirming that the inhibitory effect of these PBDEs on TCDD-induced responses was not only due to direct interaction at receptor level but also at DNA-binding level. This antagonism was confirmed for BDE-99 in HepG2 cells transiently transfected with a Gal4-AhR construct and the corresponding Gal4-Luc reporter gene. In addition, a chromatin immunoprecipitation assay further confirmed that BDE-99 could bind to the AhR and activate the AhR nuclear translocation and dioxin responsive element (DRE) binding in the context of the CYP1A1 promoter. However, the transactivation function of the BDE-99-activated AhR seems to be very weak. These combined results suggest that PBDEs do bind but not activate the AhR-AhR nuclear translocator protein-XRE complex.

Research in Veterinary Science, 1993

Journal of Veterinary Pharmacology and Therapeutics, 1996

Journal of Veterinary Pharmacology and Therapeutics, 1993

regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatme... more regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatment on plasma disposition and metabolite formation of sulphadimidine. J. vet. Pharma-601. Therap. 16, 55-62. Sulphadimidine (20 mg/kg i.v.) plasma elimination and metabolite formation were studied in intact male, castrated male, and female dwarf goats. Plasma pharmacokinetics and urinary metabolite patterns were first studied in untreated animals. Afterwards, females and castrates were treated with a combination of testosterone-propionate (1 mg/kg) and 17P-oestradiolbenzoate (0.02 mg/kg) once every 3 days, for a period of 4 weeks. In untreated animals, males showed a considerably lower plasma clearance than females or castrates. This was accompanied by lower partial clearances for the production of two hydroxylated sulphadimidine metabolites. After hormonal treatment of females and castrates, sulphadimidine plasma clearance was significantly reduced, to values corresponding with those observed in control males. Furthermore, hydroxylation was significantly inhibited after treatment. The results indicate that sulphadimidine hydroxylation in the goat is performed by enzymes of the cytochrome P450 complex which are strongly influenced by gonadal hormones. Androgens seem to play a central role in this respect.

Journal of Veterinary Pharmacology and Therapeutics, 1993

Effect of gonadal hormones o n the plasma clearanw and nietaliolite forniation of antipyrine in t... more Effect of gonadal hormones o n the plasma clearanw and nietaliolite forniation of antipyrine in the dwarf goat. ,I. vct. Pltnrmacol. T/LUU#I. 'I'he effect of' gonadal liornwies on the plasma elimination and urinary metabolite profile o f antipyrine was studied in tlwaif goats. Fernale goats were treated with testosterone a n d male goats were treated with 17fi-oestradiol. tr-atecl males were treated witti either testosterone or 17fi-oesti~atliol. Antipyrine (25 mglkg, i.v.) was given both hefore a n d after the 1ioi.inon;il treatments. T h e effects of the hormonal status on the plasma elimination of' the parent compound were not consistent. This was possibly due t o the fact that formation of' the main nietabolite of antipyrine in the goat, 4-hytltoxy aritipyrine (OHA), w;is not affected b y sex or hormonal treatnient. O n tlie other hand, there were clear effects of' hormonal status on urinary excr-etion of the t h w e other metat)olites. In females a n d castrated males testosterone suppressed tlie formation of' norantipyrine (NOKA), 3-hydroxymethylantipyrine (HMA) a n d 4,4'-dihydroxyantipyrine (DOHA). Intact males produced smaller amounts o f these rrietabolites than females. I t is concluded that distinct xenobiotic nietaholir.ing p t h w a y s exist in the dwarf' goat, which a r e influenced in their activity b y gonadal Iiorniones. This confirms previous findings in rats and mice. T h e possibility that sex hormones influence d r u g metabolisrn in fiiod-t)ro(lucing animals could have consequences for veterinary therapeutics a n d public health. This study also demonstrates that, when using the antipyrine test for the assessment of hepatic d r u g nietabolism, it is very important t o include the determination of metabolites.

Journal of Veterinary Pharmacology and Therapeutics, 1989

Journal of Veterinary Pharmacology and Therapeutics, 1988