Human Cytochrome P450 Enzyme Specificity for Bioactivation of Safrole to the Proximate Carcinogen 1'-Hydroxysafrole
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- 作者：Suzanne M. F. Jeurissen ; Jan J. P. Bogaards ; Hanem M. Awad ; Marelle G. Boersma ; Walter Brand ; Yiannis C. Fiamegos ; Teris A. van Beek ; Gerrit M. Alink ; Ernst J. R. Sudhö ; lter ; Nicole H. P. Cnubben
- 刊名：Chemical Research in Toxicology
- 出版年：2004
- 出版时间：September 2004
- 年：2004
- 卷：17
- 期：9
- 页码：1245 - 1250
- 全文大小：72K
- 年卷期：v.17,no.9(September 2004)
- ISSN：1520-5010
文摘
In the present study, the cytochrome P450 mediated bioactivation of safrole to its proximatecarcinogenic metabolite, 1'-hydroxysafrole, has been investigated for the purpose of identifyingthe human P450 enzymes involved. The 1'-hydroxylation of safrole was characterized in avariety of in vitro test systems, including Supersomes, expressing individual human P450enzymes to a high level, and microsomes derived from cell lines expressing individual humanP450 enzymes to a lower, average human liver level. Additionally, a correlation study wasperformed, in which safrole was incubated with a series of 15 human liver microsomes, andthe 1'-hydroxylation rates obtained were correlated with the activities of these microsomestoward specific substrates for nine different isoenzymes. To complete the study, a finalexperiment was performed in which pooled human liver microsomes were incubated with safrolein the presence and absence of coumarin, a selective P450 2A6 substrate. On the basis of theresults of these experiments, important roles for P450 2C9*1, P450 2A6, P450 2D6*1, andP450 2E1 were elucidated. The possible consequences of these results for the effects of geneticpolymorphisms and life style factors on the bioactivation of safrole are discussed. Polymorphismsin P450 2C9, P450 2A6, and P450 2D6, leading to poor metabolizer phenotypes, may reducethe relative risk on the harmful effects of safrole, whereas life style factors, such as the use ofalcohol, an inducer of P450 2E1, and barbiturates, inducers of P450 2C9, and polymorphismsin P450 2D6 and P450 2A6, leading to ultraextensive metabolizer phenotypes, may increasethe relative risk.