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At least 253 records · Page 14Linked to original sources
PubMed1994

Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones.

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltiprax results from enhanced transcription. In the present study, the molecular mechanisms of these inductions were analyzed utilizing a construct containing a 41 bp enhancer element derived from the 5'-upstream region of the mouse liver glutathione S-transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormone production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H: quinone reductase were also determined in Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) between the potencies of the 21 active compounds as inducers of both NAD(P)H: quinone reductase activity and growth hormone production. Moreover, no dithiolethiones were inactive in only one system. It is probable, therefore, that the induction of NAD(P)H: quinone reductase and other phase 2 enzymes by oltipraz and other dithiolethiones is mediated entirely through the 41 bp enhancer element.

Animals↗
PubMed1985

Photolysis products of 2,4,5,2',4',5'-hexabromobiphenyl: hepatic microsomal enzyme induction and toxicity in Sprague-Dawley rats.

The irradiation of 2,4,5,2',4',5'-hexabromobiphenyl (2,4,5-HBB) by ultraviolet light created a mixture of lower brominated polybrominated biphenyl (PBB) congeners. Three photoproducts, 2,4,5,3',4'-pentabromobiphenyl (-PBB), 2,4,5,2',5'-PBB, and 3,4,3',4'-tetrabromobiphenyl (3,4-TBB), as well as 2,4,5-HBB and the photolyzed 2,4,5-HBB mixture, were administered to rats as a single ip injection (90 mg/kg, except 3,4-TBB, which was given at 2 mg/kg) 2 weeks before sacrifice. All treatments except 3,4-TBB induced NADPH-cytochrome P-450 reductase and aminopyrine-N-demethylase activities while all treatments except 2,4,5-HBB induced ethoxyresorufin-O-deethylase and UDP-glucuronosyltransferase activities. Thymus to body weight and spleen to body weight ratios were unchanged compared to controls for all treatments whereas an increase in the liver weights was observed for all treatment groups. Histologic examination revealed that the photolyzed 2,4,5-HBB mixture caused moderate to severe hepatocyte enlargement. Results of tissue analysis for the pure PBB congeners indicated that 2,4,5,2',5'-PBB and 3,4-TBB were metabolized in vivo and this was confirmed by in vitro metabolism studies. The results revealed that the photolyzed 2,4,5-HBB mixture caused a mixed-type induction of hepatic drug-metabolizing enzymes. This is most likely due to the effect of 2,4,5-HBB and toxic congeners formed during the irradiation of 2,4,5-HBB. 2,4,5,3',4'-PBB, which is toxic and apparently not metabolized, is believed to be the major congener contributing to the increased toxicity of the photolyzed 2,4,5-HBB mixture since 3,4-TBB was metabolized and appeared not to be as potent as inducer of aryl hydrocarbon hydroxylase activity.

Adipose Tissue↗
PubMed1992

Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction.

The pharmacokinetics of cyclosporine was studied in six healthy volunteers after administration of the drug orally (10 mg/kg) and intravenously (3 mg/kg) with and without concomitant rifampin administration. Both blood and plasma (separated at 37 degrees C) samples were analyzed for cyclosporine concentration. For blood and plasma, respectively, clearances of cyclosporine were calculated to be 0.30 and 0.55 L/hr/kg, values for volume of distribution at steady state were 1.31 and 1.68 L/kg, and bioavailabilities were 27% and 33% during the pre-rifampin phase. Post-rifampin phase clearances of cyclosporine were 0.42 and 0.79 L/hr/kg, values for volume of distribution at steady state were 1.36 and 1.35 L/kg, and bioavailabilities were 10% and 9% for blood and plasma, respectively. Rifampin not only induces the hepatic metabolism of cyclosporine but also decreases its bioavailability to a greater extent than would be predicted by the increased metabolism. The decreased bioavailability most probably can be explained by an induction of intestinal cytochrome P450 enzymes, which appears to be markedly greater than the induction of hepatic metabolism.

Administration, Oral↗
PubMed1975

[Enzyme induction in Streptomyces hydrogenans. V. Characterization of testosterone-17 beta-dehydrogenase and its induction by steroids].

Testosterone 17beta-dehydrogenase can be enriched from Streptomyces hydrogenans. The enzyme dehydrogenizes testosterone with Km=13muM and estradiol-17beta with Km=21muM to the corresponding 17-ketoderivatives. NAD forms NADH with Km=125muM. The enzyme is strongly inhibited by androstandione and 17alpha-methyltestosterone. The Ki for 17alpha-methyltestosterone is 18muM. The enzyme activity increases with increasing pH up to alkali-mediated denaturation at about pH 10. The optimum temperature is at 45 degrees C. If Streptomyces hydrogenans is cultivated in the absence of steroids, the specific activity of testosterone 17beta-dehydrogenase in the cytosol of the microorganisms amounts to 10 mU/mg protein, and increases up to 10-fold if the cells are cultivated in the presence of certain steroids. Testosterone, alpha-dihydrotestosterone, beta-dihydrotestosterone, estradiol-17beta, and 17alpha-methyltestosterone are very effective inducers. Thus, for the first time, the ability of estradiol-17beta to induce an enzyme synthesis in a microorganism is shown. The steroid-dependent induction is inhibited by testosterone acetate and rifamycin SV. Cyproterone, however, does not decrease the testosterone-dependent enzyme induction of testosterone 17beta-dehydrogenase.

Androstane-3,17-diol↗