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© 1995 Oxford University Press

research-article

Procarcinogen activation by cytochrome P450 3A4 and 3A5 expressed in Escherichia coli and by human liver microsomes

Hiroshi Yamazaki, Yukiharu Inui 1, Steven A. Wrighton 2, F.Peter Guengerich 3 and Tsutomu Shimada 4

Osaka Prefectural Institute of Public Health 3-69 Nakamichi 1-chome, Higashinan-ku, Osaka 537, Japan
1Center for Adult Diseases Osaka Higashinari-ku, Osaka 537, Japan
2Department of Drug Metabolism and Disposition, Eli Lilly and Company Indianapolis, IN 46285
3Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine Nashville, TN 37232, USA

4To whom reprint requests should be addressed

Recent studies indicate that cytochrome P450 (P450) 3A4 plays important roles in the activation of procarcinogens such as aflatoxin B1 and sterigmatocystin, as well as in the oxidation of a number of structurally diverse chemicals and endogenous compounds. Since P450 3A5 has been reported to be present at significant levels in liver microsomes in ~25% of human adults, we examined and compared the role of P450 3A4 and 3A5 in procarcinogen activation in humans. Immunoblot experiments with liver microsomes from 60 human samples suggested that 4/30 Japanese and 4/30 Caucasians contained considerable levels of P450 3A5, although P450 3A4 could be determined at relatively high levels in all of the human samples examined. Good correlation was observed between P450 3A4, but not P450 3A5, levels versus activation of aflatoxin B1 and stergmatocystin in these human samples. Comparisons of the activation of procarcinogens in reconstituted monooxy-genase systems containing modified P450 3A4 and 3A5 enzymes expressed in Escherichia coli were carried out in Salmonella typhimurium TA1535/pSK1002 or NM2009 tester strain for genotoxicity assay, and it was found that P450 3A4 had similar activities to or higher rates than P450 3A5 for the 24 procarcinogens tested.


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