Human cytochrome P450 enzyme specificity for bioactivation of safrole to the proximate carcinogen 1′-hydroxysafrole

被引:60
作者
Jeurissen, SMF
Bogaards, JJP
Awad, HM
Boersma, MG
Brand, W
Fiamegos, YC
van Beek, TA
Alink, GM
Sudhölter, EJR
Cnubben, NHP
Rietjens, IMCM
机构
[1] Wageningen Univ, Div Toxicol, NL-6703 HE Wageningen, Netherlands
[2] Wageningen Univ, Organ Chem Lab, NL-6703 HB Wageningen, Netherlands
[3] TNO, Nutr & Food Res, NL-3700 AJ Zeist, Netherlands
[4] Wageningen Univ, Biochem Lab, NL-6703 HA Wageningen, Netherlands
[5] WU TNO, Ctr Food Toxicol, NL-6700 EA Wageningen, Netherlands
[6] Natl Res Ctr, Dept Chem Tanning Mat & Prot, Cairo, Egypt
关键词
D O I
10.1021/tx040001v
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In the present study, the cytochrome P450 mediated bioactivation of safrole to its proximate carcinogenic metabolite, 1'-hydroxysafrole, has been investigated for the purpose of identifying the human P450 enzymes involved. The 1'-hydroxylation of safrole was characterized in a variety of in vitro test systems, including Supersomes, expressing individual human P450 enzymes to a high level, and microsomes derived from cell lines expressing individual human P450 enzymes to a lower, average human liver level. Additionally, a correlation study was performed, in which safrole was incubated with a series of 15 human liver microsomes, and the 1'-hydroxylation rates obtained were correlated with the activities of these microsomes toward specific substrates for nine different isoenzymes. To complete the study, a final experiment was performed in which pooled human liver microsomes were incubated with safrole in the presence and absence of coumarin, a selective P450 2A6 substrate. On the basis of the results of these experiments, important roles for P450 2C9*1, P450 2A6, P450 2D6*1, and P450 2E1 were elucidated. The possible consequences of these results for the effects of genetic polymorphisms and life style factors on the bioactivation of safrole are discussed. Polymorphisms in P450 2C9, P450 2A6, and P450 2D6, leading to poor metabolizer phenotypes, may reduce the relative risk on the harmful effects of safrole, whereas life style factors, such as the use of alcohol, an inducer of P450 2E1, and barbiturates, inducers of P450 2C9, and polymorphisms in P450 2D6 and P450 2A6, leading to ultraextensive metabolizer phenotypes, may increase the relative risk.
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页码:1245 / 1250
页数:6
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