Regulation of uridine diphosphate glucuronosyltransferase during the acute-phase response (original) (raw)
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Journal of Biological Chemistry, 1996
Transcription factors AP-1 and NF-B have been implicated in the inducible expression of a variety of genes in response to oxidative stress. Recently, based on the observation that butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC) induce AP-1 binding activity and AP-1-dependent gene expression and assuming that these compounds exert an antioxidant effect, it was claimed that AP-1 is an antioxidant-responsive factor. To determine whether AP-1 can be responsive to both oxidant and antioxidant, we examined the nature of BHA and PDTC inducing activity. Using EPR spectroscopy to detect semiquinone radicals, we demonstrate the autoxidation of BHA metabolite tert-butylhydroquinone (TBHQ) to tert-butylquinone.
International Journal of Cancer, 1997
There is a growing need for short-term and cost-effective bioassay to assess the efficacy of potential chemo-preventive agents. We report that the induction of glutathione (GSH) S-transferase (mGSTP1-1) by a chemo-preventive agent can be used as a reliable marker to assess its efficacy in retarding chemical carcinogenesis induced by benzo(a)pyrene (BP), which is a widespread environmental pollutant and believed to be a risk factor in human chemical carcinogenesis. This conclusion is based on 1) the relative contribution of mGSTP1-1 of the liver and forestomach of female A/J mice in the detoxification of the ultimate carcinogenic metabolite of BP, (؉)-anti-7,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(؉)-anti-BPDE]; and 2) a positive correlation between the induction of hepatic and forestomach mG-STP1-1 by 5 naturally occurring organosulfides (OSCs) from garlic (diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl disulfide) and their effectiveness in preventing BP-induced forestomach neoplasia in mice. In the liver, the combined contribution of other GSTs in the detoxification of (؉)-anti-BPDE was far less than the contribution of mGSTP1-1 alone. Likewise, in the forestomach, the contribution of mGSTP1-1 far exceeded the combined contribution of other GSTs. Studies on the effects of OSCs against BPinduced forestomach neoplasia revealed a good correlation between their chemo-preventive efficacy and their ability to induce mGSTP1-1 expression in the liver (r ؍ ؊0.89; p F 0.05) as well as in the forestomach (r ؍ ؊0.97; p F 0.05). Our results suggest that the induction of mGSTP1-1 may be a reliable marker for evaluating the efficacy of potential inhibitors of BP-induced cancer in a murine model. Int.
Chemoprevention of heterocyclic amine-induced carcinogenesis by phenolic compounds in rats
Cancer Letters, 1999
Chemopreventive effects of synthetic and naturally occurring antioxidants on heterocyclic amine (HCA)-induced rat carcinogenesis and mechanisms of inhibition were assessed. In a medium-term liver bioassay, combined treatment with 0.03% 2amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and synthetic antioxidants such as 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), BHA, BHT, tert-butylhydroquinone (TBHQ) and propyl gallate, each at a dose of 0.25%, and troglitazone at doses 0.5 and 0.1%, potently inhibited development of glutathione S-transferase placental form (GST-P) positive foci as compared with MeIQx alone values. Of these antioxidants, HTHQ showed the greatest activity. Green tea catechins tended to inhibit GST-P positive foci development, while quercetin, rutin, curcumin, daidzin, ferulic acid and genistin all exerted signi®cant enhancing effects. HTHQ also inhibited 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colon carcinogenesis in a two stage colon carcinogenesis model using 1,2-dimethylhydrazine (DMH) as an initiator. Immunohistochemically detected PhIP±DNA adduct positive nuclei in the colon induced by continuous oral treatment with 0.02% PhIP for 2 weeks decreased by the combined treatment with 0.5 or 0.125% HTHQ. Methoxyresor®n O-demethylase activity in rat liver microsomes in vitro was clearly inhibited by the addition of HTHQ, BHA, BHT, TBHQ or propyl gallate, with particularly strong inhibition being observed in HTHQ. However, the CYP1A2 level in rat liver increased after oral treatment with HTHQ for 2 weeks. These results indicate that synthetic antioxidants, HTHQ in particular, is a very strong chemopreventor of HCAinduced carcinogenesis. It is suggested that depression of metabolic activation rather than antioxidant activity is responsible for the observed effect. However, other mechanisms, including the effects on phase II enzymes cannot be ruled out. q
Pakistan Journal of Medical Sciences Online
The effect of benzo(a)pyrene (BaP) on the activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx) and histology in the liver and kidney of the mouse, Mus musculus were investigated. Three treatment groups of mice (6 in each group) were injected with 200mg/kg BaP once a week. Groups 1,2 and 3 were sacrificed after two, four and eight weeks, respectively by cervical dislocation. Similarly three control groups of mice injected with corn-oil were sacrificed at week 2, week 4 and week 8. Sections of the liver and kidney of mice were stained with hematoxylin and eosin. The GST activity in the liver and kidney was significantly increased after two weeks compared to the control group (P<0.05). The GPx activity in the liver significantly increased to a maximum at four weeks. After eight weeks, GST and GPx activities decreased in the treated mice liver compared to the control group. Grey-white hyperplastic nodules were visible in the liver after four weeks of treatment. The slides prepared from these tissues showed marked morphological changes where the hepatocytes were paler, more vacuolated and had lost their normal shape and arrangement. The kidney cells showed mild inflammation within the medulla and glomeruli after four weeks. After eight weeks severe inflammation was observed in medulla but there was no change in the other parts. In this study, it was found that differences in morphology and cellular changes in liver and kidney were time dependent. It is concluded that assay of GST activity provides a method to monitor antioxidant changes in mice liver and kidney after exposure to BaP. The result indicated that liver was main target for chemically induced toxicity.
Modifying Effects of Antioxidants on Chemical Carcinogenesis
Toxicologic Pathology, 1986
Studies were made on the carcinogenic activity of butylated hydroxyanisole (BHA) in rats, mice, and hamsters and the effect of the antioxidants BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), sodium L-ascorbate (SA), ascorbic acid (AA), sodium erythorbate (SE), propyl gallate (PG), and α-tocopherol, on two-stage chemical carcinogenesis in rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 1,2-dimethylhydrazine (DMH), diethylnitrosamine (DEN), 7,12-dimethylbenz(a)anthracene (DMBA), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), N-ethyl-N-hydroxyethylnitrosamine (EHEN), or N-methylnitrosourea (MNU). BHA clearly induced squamous cell carcinomas in both the rat and hamster forestomach. The tumorigenic action of crude BHA on the forestomach is largely due to 3- tert-BHA. In two-stage chemical carcinogenesis, BHA promoted MNNG or MNU-initiated forestomach and BBN- or MNU-initiated urinary bladder carcinogenesis and inhibited DEN- or EHEN-initiated liver and DMBA-init...
Biochemical Pharmacology, 1979
The ubiquitous environmental pollutant benzo(a)pyrene is metabolized by cytocbrome P-450 dependent monooxygenases to various electrophilic intermediates which either spontaneously rearrange to phenols or are converted by epoxide hydratase to dihydrodiols. These primary metabolites may recycle a second time through monooxygenases whereby probably the ultimate carcinogens are formed (l-3). Conjugation with glucuronic acid or sulfate helps to eliminate primary metabolites and thus prevents recycling. A delicate balance between toxifyfng and detoxifying reactions may be decisive for the accumulation of ultimate carcinogens.
Microsomal UDP-Glucuronyltransferase in Rat Liver: Oxidative Activation
Basic & Clinical Pharmacology & Toxicology, 2005
Activation of microsomal UDP-glucuronyltransferase (UDPGT) activity by treatment of hepatic microsomes with either detergents or Fe 3π /ascorbate pro-oxidant system has been reported; however, definite mechanisms underlying these effects have not been clarified. In this work, we characterize Fe 3π /ascorbate-induced activation of UDPGT activity prior to solubilization with Triton X-100 and after the oxidation process provoked the solubilization of the enzyme. We observed a time-dependent increase in UDPGT activity up to 20 min. incubation of the microsomes with Fe 3π /ascorbate (3-times); after 20 min. incubation, however, we observed a time-dependent decrease in this activity to basal levels after 4 hr incubation. Treatment of microsomes with 0.1% Triton X-100 (5 min.) lead to a similar increase in UDPGT activity; higher detergent concentrations produced a dose-dependent decrease in this activity to basal levels with 1% Triton X-100. Interestingly, UDPGT activity was susceptible to activation only when associated to microsomal membranes and the loss of activation correlated with the solubilization of this activity. UDPGT activation by either Fe 3π /ascorbate or Triton X-100 was correlated with an increase in p-nitrophenol apparent K m and V max values. This activation was prevented or reversed by the reducing agents glutathione, cysteine or dithiothreitol when it was induced by the Fe 3π /ascorbate. Furthermore, the latter provoked a significant decrease in microsomal thiol content, effect not observed after treatment with Triton X-100. Our results suggest that the main mechanism responsible for Fe 3π /ascorbate-induced UDPGT activation is likely to be the promotion of protein sulfhydryl oxidation; this mechanism appears to be different from detergent-induced UDPGT activation.