Species differences in the in vitro metabolic activation of the hepatotoxic pyrrolizidine alkaloid clivorine
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香港中文大學研究人員

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摘要Clivorine is a representative naturally occurring hepatotoxic otonecine-type pyrrolizidine alkaloid. Our previous study has demonstrated that clivorine induces liver damage via metabolic activation to form the reactive pyrrolic ester followed by covalent binding to liver tissue constituents. The present study investigated species differences in the in vitro metabolic activation of clivorine in the male rat and guinea pig of both sexes. In the male rat, the activation of clivorine to form the reactive pyrrolic ester was found as the only metabolic pathway. Moreover, the toxic tissue-bound pyrroles and four isolatable metabolites identified, namely DHR, 7-GSH-DHR; 7,9-diGSH-DHR, and clivoric acid, were all generated from further metabolism of this reactive intermediate. In the case of both sexes of guinea pig, the same activation was observed as the minor biotransformation, while an additional metabolic pathway, a direct hydrolysis of clivorine to form novel clivopic acid was identified as the predominant detoxification pathway. Furthermore, the formation rates for the toxic tissue-bound pyrroles and less toxic DHR were significantly slower and higher, respectively, compared with those in the male rat. In addition, the formation of the reactive pyrrolic ester was mediated by the CYP3A subfamily in both animals, while carboxylesterases might be responsible for the detoxification hydrolysis in guinea pig. The results suggest that the higher metabolic rates for detoxification hydrolyses and the lower formation rate for the toxic tissue-bound pyrroles play the key roles in guinea pig resistance to clivorine intoxication. Therefore, the male rat and guinea pig should be the suitable animal models for further studies of bioactivation and deactivation of otonecine-type PA, respectively.
著者Lin G, Cui YY, Liu XQ, Wang ZT
期刊名稱Chemical Research in Toxicology
詳細描述vol.15
出版年份2002
月份11
日期1
卷號15
期次11
出版社AMER CHEMICAL SOC
頁次1421 - 1428
國際標準期刊號0893-228X
電子國際標準期刊號1520-5010
語言英式英語
Web of Science 學科類別Chemistry; Chemistry, Medicinal; CHEMISTRY, MEDICINAL; Chemistry, Multidisciplinary; CHEMISTRY, MULTIDISCIPLINARY; Pharmacology & Pharmacy; Toxicology; TOXICOLOGY

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