Nature of the enhancement of hepatic uridine diphosphate glucuronyltransferase activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats (original) (raw)
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Archives of Toxicology, 1999
Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains Abstract Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)induced lethality in rats. This study was carried out to further analyse the toxicological signi®cance of reduced gluconeogenesis by comparing dose-responses and timecourses of eects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations of glucose and amino acids in both genders of TCDD-sensitive Long-Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependent decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in liver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This eect seems to be secondary to reduced feed intake, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less aected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to re¯ect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity dierence of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is dierent from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.
Promotion of Enzyme Altered Foci in Female Rat Livers by 2,3,3′,4,4′,5-Hexachlorobiphenyl
Toxicology and Applied Pharmacology, 1997
PCBs constitute a group of 209 different congeners and The tumor promoting activity of 2,3,3,4,4,5-hexachlorobiphenyl the numbers and sites of chlorine substitution determine the (PCB 156) was studied in an initiation/promotion bioassay in female chemical and biological characteristics of a specific conge-Sprague-Dawley rats initiated with N-nitrosodiethylamine after parner. The most toxic PCBs are those substituted in both para tial hepatectomy. PCB 156 (50, 300, 1500, or 7500 mg/kg body weight/ and at least two meta positions (Fig. 1). If these toxic congeweek) was administered by once-weekly subcutaneous injections for ners lack chlorine substituents in the ortho positions they 20 weeks. Some high dose animals were left without treatment for can assume a coplanar conformation and are thereby approxan additional 20 weeks to study posttreatment effects. The volume imate stereoisomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin fraction of the liver occupied by glutathione S-transferase P-positive (TCDD) (Bandiera et al., 1982; Safe et al., 1985a). These foci was significantly increased to 2.9, 3.3, and 12% at 300, 1500, coplanar PCB congeners also cause biological effects resemand 7500 mg/kg body weight/week, respectively, compared to 1.2% bling those reported for TCDD, including the induction of in the controls. The volume fraction was 43% in the high dose group 20 weeks after treatment was stopped, probably reflecting the slow the monooxygenase enzymes cytochrome P450 1A1 body clearance of PCB 156 as indicated by the sustained liver and (CYP1A1) and CYP1A2, skin lesions, thymus atrophy, liver adipose tissue concentrations. Treatment with PCB 156 following damage, and a wasting syndrome (reviewed by Safe, 1990). initiation caused decreased body weight gain, thymic atrophy, liver If one or more chlorine substituents are introduced in an enlargement, induction of hepatic cytochrome P450 1A1/2 (CYP1A1/ ortho position, a decreased degree of coplanarity between 2) and CYP2B1/2 activities, histopathological effects, and increased the two phenyl rings will occur due to steric interactions. activities of aspartate aminotransferase and g-glutamyltransferase in Mono-ortho-chloro PCBs induce toxic effects that qualitaplasma. These results show that PCB 156 can enhance the growth tively resemble the toxicity of TCDD, but in addition to of altered foci in rat liver and probably act as a tumor promoter of the monooxygenases induced by TCDD, the mono-orthohepatocarcinogenesis. Based on promotional activity a relative posubstituted PCBs also induce CYP2B1 and/or CYP2B2 (Safe tency of PCB 156 to 2,3,7,8-tetrachlorodibenzo-p-dioxin of 0.0001-0.001 is proposed.
Chemosphere, 1992
The disposition, elimination and cytochrome P450 related enzyme induction of 1,2,3,7,8pentachlorodibenzo-p-dioxin (PnCDD), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) and 2,3,4,7,8pentachlorodibenzofuran (PnCDF) were studied in the liver of the male C57BL/6 mouse. Elimination of all compounds from the liver followed first-order kinetics. Half-lives for PnCDD, HxCDD and PnCDF were 15, 52 and 65 days respectively. 7-Ethoxyresorufin-O-deethylation (EROD) activity in the livers of the treated animals showed a good correlation with the liver tissue concentrations but the slopes of these liver concentration-response curves were not equal for all three compounds.
Drug metabolism and …, 2000
Induction of UDP-glucuronosyltransferases (UGTs) toward thyroxine (T4) and p-nitrophenol (pNP) by 3-methylcholanthrene (MC), dexamethasone (DEX), clofibrate (Cl), and MC combined with DEX or Cl was studied in rat hepatocyte culture. We have developed a sensitive method for the measurement of glucuronide conjugates of the two substrates based on HPLC analysis of culture medium. MC, Cl, or DEX increased the activity of T4 UGT. Combination of MC and Cl showed additive effect, enzyme activity was enhanced compared with either MC or Cl treatment alone (617, 441, and 217% of the control, respectively). Combination of MC and DEX did not result in higher T4 UGT activity than MC treatment alone. Both MC and DEX enhanced the pNP UGT activity (182 and 162% of the control, respectively). Combination of MC with DEX resulted in additive effect. Cl treatment did not affect pNP conjugation either alone or in combination with MC. Western blot analysis revealed that only the amount of UGT1A1 was elevated by Cl and DEX. In contrast, concentration of UGT1A6 was increased by MC. Previous studies demonstrated that UGT1A1 inducers like phenobarbital have no effect on T4 conjugation (Saito et al., 1991). Our results suggest that Cl, a known inducer of UGT1A1, enhances the activity of other enzyme(s) involved in T4 glucuronidation as well. It is well documented that DEX potentiates the inductory effect of polycyclic aromatic hydrocarbon on UGT1A6 (Xiao et al., 1995). In our study, MC increased the rate of T4 glucuronidation, and DEX had no additional effect on this reaction, suggesting that UGT1A6 is not the only enzyme inducible by MC that can catalyze T4 conjugation.
Biochem Pharmacol, 1986
The temporal and dose-related characteristics of hepatic enzymes induced in the hamster by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined. Male Syrian golden hamsters received a single intraperitoneal injection of TCDD at a dose of O-500 pg/kg. At various times up to 35 days, a number of variables were determined and compared: whole body, liver, and thymus weights; hepatic ~n~ntrations of cytochrome P-450 (P-450); and activities of 7-ethoxyco~a~n 0-deethylase @COD) and reduced NAD(P) : menadione oxidoreductase (NMOR). Increased liver weights and decreased thymus weights were observed to be dose related. At day 7 following treatment, the approximate EDso values for these responses were 15 and 100 &kg respectively. The EDGE values for the increase in hepatic P-450 concentrations and activities of ECOD and NMOR ranged from 0.5 to 2.0 pg/kg. At 10 and 500 hg/kg, NMOR activity remained maximally induced for up to 35 days. This was also the case for P-450 and ECOD ac!$ity at a dose of lOlg/kg. At SOOpg/kg, both P-450 and ECOD demonstrated an induction up to day 4 followed by a decrease to near control levels by day 14. This decrease appeared to correlate with changes in hepatic mo~holo~. These results demonstrate a disso~ation of the induction of these hepatic enzymes from TCDD-induced lethality, in this species.
Toxicology and Applied Pharmacology, 1981
Toxicol. Appl. Pharmacol. 61, 109-l 18. A comparative study of the induction patterns of rat hepatic microsomal mixed-function oxidases was carried out in male Sprague-Dawley rats. The pattern of induction by DDT was different from that of phenobarbital. First, DDT induction was not acompanied by an increase in d-aminolevulinic acid synthetase, and, second, it was not affected by prior treatment with actinomycin D or a-amanitin in vivo. Otherwise, induction by these two chemicals as determined by differential increases in various drug-metabolizing activities and cytochrome P-450 was indistinguishable, indicating the basic similarities of these two induction patterns. Both TCDD and 3-methylcholanthrene (3-MC) induced a similar type of change in the cytochrome as judged by ethyl isocyanide-and CO-binding spectra. However, induction by TCDD and 3-MC was also different in two important areas: first, induction by 3-MC was inhibited by a prior or simultaneous treatment with actinomycin D, while that by TCDD was not. Second, the pH response of the induced cytochrome P-448 in terms of ethyl isqcyanide-binding spectral changes was different in the two cases.
Toxicology, 1985
The effect of thyroidectomy and thyroid hormone replacement therapy on liver microsomal enzyme induction was studied in 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (100 micrograms/kg). Treatment of non-thyroidectomized rats with TCDD had no effect on the concentration of liver microsomal cytochrome b5. In contrast, cytochrome b5 content was increased by TCDD treatment of thyroidectomized rats, regardless of replacement therapy with either T3 or T4. TCDD treatment increased the concentration of cytochrome P-450 (2-3-fold) and the activities of benzo[a]pyrene hydroxylase (4-7-fold), ethoxyresorufin O-de-ethylase (50-70-fold) and UDP-glucuronosyltransferase (5-7-fold) in non-thyroidectomized and thyroidectomized as well as thyroidectomized thyroid hormone treated rats; indicating the induction of these liver microsomal enzyme activities is independent of thyroid status. Because thyroid status alters the toxicity of TCDD but does not alter the ability of TCDD to induce micr...
Chemico-Biological Interactions, 1975
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) administered to pregnant rats at 3 pg/kg as a single oral dose during early, middle, or late gestation caused marked elevations of some maternal hepatic microsomal enzymes for at least 10 weeks after treatment. This dose was not teratogenic and fetal rates of glucuronidation of testosterone and p-nitrophenol (PNP) were unaffected. Increases in fetal liver benzpyrene hydroxylase (BPH) activities were evident during late gestation although cytochrome P-450 and cytochrome b5 contents were unchanged. The offspring of pregnant rats administered TCDD had markedly elevated hepatic PNP UDPglucuronyltransferase (UDPGT) BPH, and microsomal cytochrome contents whereas the perinatal development of testosterone UDPGT was unchanged. PNP giucuronidation attained a maximal 8-fold increase above controls by 3 weeks after birth and activities were twice that of controls 8 weeks after birth (adults). Maximal increases in benzpyrene hydroxylation rates occurred one day after birth when in the prenatally exposed group activities were approximately 20 times higher than controls. Foster mother experiments demonstrated that the postnatal inductive effect resulted both from exposure of newborns to TCDD via maternal milk and the activation of an inducing mechanism occurring after birth. These data demonstrate that multiple factors are responsible for the induction of hepatic microsomal enzymes in the newborn following administration of TCDD to pregnant rats.