Coumarin mercapturic acid isolated from rat urine indicates metabolic formation of coumarin 3,4-epoxide

Huwer, Thomas; Altmann, Hans; Grunow, W.; Lenhardt, Susanne; Przybylski, Michael; Eisenbrand, Gerhard

doi:10.1021/tx00023a016

Cited by 26 publications

(9 citation statements)

References 7 publications

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“…The changes in GSH content and activities of GSH 5-transferase and y-glutamyltransferase may be attributed to enhanced detoxification of a coumarin 3,4-epoxide and possibly other reactive intermediates by formation of GSH conjugates. Coumarin is known to enhance urinary mercapturic acid excretion in the rat (Lake, 1984) and a coumarin mercapturic acid metabolite has been identified in rat urine (Huwer et al, 1991).…”

Section: Weeksmentioning

confidence: 99%

Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

Lake

Grasso

1996

Toxicol Sci

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The effects of coumarin treatment have been compared in male Sprague-Dawley CD rats, male CD-I mice, and male Syrian hamsters. Rats were fed 0-0.75% coumarin for 1 and 4 weeks and 0-0.5% coumarin for 13 weeks, whereas mice and Syrian hamsters were fed 0-0.5 and 0-1.0% coumarin, respectively, for periods of 1, 4, and 13 weeks. In the rat, coumarin produced dose-related hepatotoxic effects which included vacuolar degeneration, apoptosis, and bile duct proliferation. These effects were particularly marked at dose levels of 0.3 and 0.5%, where liver tumors have been observed in a chronic study. Coumarin administration to rats also increased serum bilirubin content and both serum and hepatic y-glutamyltransferase activity. While levels of hepatic total glutathione were increased by coumarin administration, microsomal cytochrome P450 content and ethylmorphine N-demethylase activity were reduced. Such effects were either less marked or absent in the mouse and Syrian hamster. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine during Study Weeks 0-1, 3-4, and 12-13. In the rat, coumarin administration for 4 and 13 weeks at dose levels of 0.3 and 0.5% produced a sustained stimulation of hepatocyte replicative DNA synthesis. No such effects were observed in the mouse and Syrian hamster. These results demonstrate marked species differences in coumarin-induced hepatotoxicity. While tumor formation in the rat appears due to chronic hepatotoxicity associated with a sustained regenerative hyperplasia, such effects were not observed in the CD-I mouse and Syrian hamster. In assessing the hazard of coumarin to humans, account needs to be taken of both levels of exposure and species differences in response, o Coumarin (1,2-benzopyrone, cw-o-coumarinic acid lactone) is a white crystalline powder and occurs naturally in

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Section: Weeksmentioning

confidence: 99%

Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

Lake

Grasso

1996

Toxicol Sci

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“…Huwer and colleagues (1990) reported the discovery of this biotransformation as the metabolite N -acetyl- S -(3-cumarinil)-cysteine (also known as 3-coumarin mercapturic acid) in the urine of rats given coumarin. The authors suggested that 3-coumarin mercapturic acid is derived from coumarin 3,4-epoxide, which is considered responsible for the toxicity of coumarin in rats and is part of a minor metabolism route in humans [ 26 ]. In our study, the chromatographic peak that corresponds to the conjugation of coumarin with N -acetylcysteine did not suggest relevant amounts of this metabolite.…”

Section: Discussionmentioning

confidence: 99%

New Metabolites of Coumarin Detected in Human Urine Using Ultra Performance Liquid Chromatography/Quadrupole-Time-of-Flight Tandem Mass Spectrometry

et al. 2017

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Coumarin (1,2-benzopyrone) is a natural compound whose metabolism in humans was established in the 1970s. However, a new metabolite was recently identified in human plasma, indicating that the metabolism of coumarin has not been completely elucidated. To complement the knowledge of its metabolism, a rapid and sensitive method using UPLC-QTOF-MS was developed. A total of 12 metabolites was identified using MetaboLynxTM software, including eight metabolites not previously reported in human urine. The identified biotransformation included hydroxylation, glucuronidation, sulfation, methylation, and conjugation with N-acetylcysteine. The present work demonstrates that the metabolism study of coumarin was incomplete, possibly due to limitations of old techniques. The identification of eight inedited metabolites of such a simple molecule suggests that the information regarding the metabolism of other drugs may also be incomplete, and therefore, new investigations are necessary.

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“…From Vitamin K epoxide reductase enzyme (VKOR) studies, it is known that there is a warfarin-sensitive thiol redox center in VKOR enzyme complex (Fasco et al, 1983), and that exposure of microsomal enzymes to thiols prevents the inhibitory effects of warfarin in this system (Wallin and Martin, 1985). Decrease in GSH content might be related to the process of warfarin detoxication/excretion, as glutathione conjugates are among major coumarin metabolites noted in rat studies (Huwer et al, 1991). These and recent data, which demonstrated the existence of warfarin-sensitive glutathione S-transferase (GST) in VKOR enzyme complex (Cain et al, 1997), might be related to the activities of warfarin described in the present study.…”

Section: Discussionmentioning

confidence: 99%

Dermatotoxicity of epicutaneously applied anticoagulant warfarin

et al. 2005

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Coumarin mercapturic acid isolated from rat urine indicates metabolic formation of coumarin 3,4-epoxide

Cited by 26 publications

References 7 publications

Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

Comparison of the Hepatotoxicity of Coumarin in the Rat, Mouse, and Syrian Hamster: A Dose and Time Response Study

New Metabolites of Coumarin Detected in Human Urine Using Ultra Performance Liquid Chromatography/Quadrupole-Time-of-Flight Tandem Mass Spectrometry

Dermatotoxicity of epicutaneously applied anticoagulant warfarin

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