In vivo metabolites of S-(2-benzothiazolyl)-L-cysteine as markers of in vivo cysteine conjugate beta-lyase and thiol glucuronosyl transferase activities.
Cysteine conjugate beta-lyases (beta-lyase), enzymes that are present in mammalian liver, kidneys, and intestinal microflora, were exploited recently for site-selective delivery of 6-mercaptopurine to the kidneys. In this study, in vivo beta-lyase activity was assessed using S-(2-benzothiazolyl)-L-cysteine (BTC). 2-Mercaptobenzothiazole and 2-mercaptobenzothiazole S-glucuronic acid were major metabolites of BTC in rat liver, kidney, plasma, and urine. Total metabolite concentrations in liver, kidney, or plasma at 30 min were similar and were higher than that detected at 3 hr; metabolites were mostly in the glucuronide form. The portions of metabolites excreted in urine at 8 and 24 hr were nearly 93 and 99% of that excreted at 40 hr, respectively. Pretreatment of rats with aminooxyacetic acid did not alter kidney, liver, plasma, or urinary metabolite concentrations. The portion of the BTC dose excreted as metabolites at 24 hr was independent of the BTC dose (100-400 mumol/kg), age (5-12 weeks), or sex of the rats. The rates of in vitro BTC metabolism by guinea pig hepatic and renal beta-lyases were slower than those of rats, but the portion of the BTC dose recovered as metabolites in guinea pig urine at 24 hr was nearly 60%, which was nearly 2-fold higher than that recovered in urine of rats, mice, or hamsters. The amounts of total metabolites excreted into urine by mice or hamsters were similar, but the portion of metabolites that was in the glucuronide form in hamster urine was higher than that in mouse urine.(ABSTRACT TRUNCATED AT 250 WORDS)
Elfarra
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Department of Comparative Biosciences and Environmental Toxicology Center, University of Wisconsin-Madison 53706.
Hwang
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IY
D000818:Animals; D015415:Biomarkers; D013437:Carbon-Sulfur Lyases; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006168:Guinea Pigs; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008190:Lyases / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013045:Species Specificity
D015415:Biomarkers; D014453:Glucuronosyltransferase; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase