In Vitro and in Vivo Studies on Acyl-Coenzyme A-Dependent Bioactivation of Zomepirac in Rats

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• 作者：J//pubs.acs.org/images/gifchars/oslash.gif" border="0">rgen Olsen ; Chunze Li ; Inga Bj//pubs.acs.org/images/gifchars/oslash.gif" border="0">rnsdottir ; Ulrik Sidenius ; Stee
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：November 2005
• 年：2005
• 卷：18
• 期：11
• 页码：1729 - 1736
• 全文大小：180K
• 年卷期：v.18,no.11(November 2005)
• ISSN：1520-5010

文摘

Zomepirac [ZP, 5-(chlorobenzoyl)-1,4-dimethylpyrrole-2-acetic acid] was withdrawn from themarket because of unpredictable allergic reactions that may have been caused by ZP-proteinadducts formed by reaction of the reactive acyl glucuronide of ZP (ZP-O-G) with endogenousproteins. To test the hypothesis that the reactive ZP acyl coenzyme A thioester (ZP-CoA) wasformed and potentially could contribute to formation of ZP-protein adducts, we investigatedthe acyl CoA-dependent metabolism of ZP in freshly isolated rat hepatocytes (1 mM) and invivo (100 mg ZP/kg, ip) in rat livers (2 h after dose administration), rat bile (0-4 h), and raturine (0-24 h). ZP-CoA was detected in freshly isolated hepatocytes and in vivo in rat liversby LC/MS/MS. In addition, the ZP glycine conjugate (ZP-Gly) and ZP taurine conjugates (ZP-Tau) were identified by LC/MS/MS in rat hepatocytes and in vivo in rat livers, rat urine, andrat bile. The identities of ZP-CoA, ZP-Gly, and ZP-Tau were confirmed by comparison ofretention times and MS/MS spectra with those of authentic standards. Moreover, the ZP acylcarnitine ester was detected in rat urine and rat bile based upon (i) the chlorine isotope pattern,(ii) MS/MS spectra showing significant ions characteristic for carnitine (m/z 60, 144 and lossof m/z 59) and ZP (m/z 139), and (iii) accurate mass measurements with a mass accuracy of0.2 ppm. ZP-CoA serves as an obligatory intermediate in the formation of ZP-Gly, ZP-Tau,and ZP carnitine ester, and it is therefore of mechanistic significance that these conjugateswere identified. Finally, time-dependent concentration profiles obtained in experiments withrat hepatocytes and in vivo from quantitative analysis of rat livers indicate that ZP-CoA, inaddition to ZP-O-G, may contribute to formation of the potentially toxic covalent ZP-proteinadducts.