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Human cytochrome P450 enzyme specificity for the bioactivation of estragole and related alkenylbenzenes

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Author: Jeurissen, S.M.F. · Punt, A. · Boersma, M.G. · Bogaards, J.J.P. · Fiamegos, Y.C. · Schilter, B. · Bladeren, P.J. van · Cnubben, N.H.P. · Rietjens, I.M.C.M.
Institution: TNO Kwaliteit van Leven
Source:Chemical Research in Toxicology, 5, 20, 798-806
Identifier: 239964
doi: doi:10.1021/tx700012d
Keywords: Biology · Biomedical Research · 1' hydroxyestragole · alkenylbenzene derivative · alpha naphthoflavone · benzene derivative · cytochrome P450 1A2 · cytochrome P450 2A6 · cytochrome P450 2C19 · cytochrome P450 2D6 · cytochrome P450 2E1 · estragole · methyleugenol · safrole · article · enzyme specificity · human · human cell · hydroxylation · liver microsome · phenotype · protein expression · Anisoles · Biotransformation · Chromatography, High Pressure Liquid · Cytochrome P-450 Enzyme System · Enzyme Inhibitors · Eugenol · Flavoring Agents · Humans · Hydroxylation · Microsomes, Liver · Safrole · Substrate Specificity


Human cytochrome P450 enzymes involved in the bioactivation of estragole to its proximate carcinogen 1′-hydroxyestragole were identified and compared to the enzymes of importance for 1′-hydroxylation of the related alkenylbenzenes methyleugenol and safrole. Incubations with Supersomes revealed that all enzymes tested, except P450 2C8, are intrinsically able to 1′-hydroxylate estragole. Experiments with Gentest microsomes, expressing P450 enzymes to roughly average liver levels, indicated that P450 1A2, 2A6, 2C19, 2D6, and 2E1 might contribute to estragole 1′-hydroxylation in the human liver. Especially P450 1A2 is an important enzyme based on the correlation between P450 1A2 activity and estragole 1′-hydroxylation in human liver microsomal samples and inhibition of estragole 1′-hydroxylation by the P450 1A2 inhibitor α-naphthoflavone. Kinetic studies revealed that, at physiologically relevant concentrations of estragole, P450 1A2 and 2A6 are the most important enzymes for bioactivation in the human liver showing enzyme efficiencies (kcat/Km) of, respectively, 59 and 341 min-1 mM-1. Only at relatively high estragole concentrations, P450 2C19, 2D6, and 2E1 might contribute to some extent. Comparison to results from similar studies for safrole and methyleugenol revealed that competitive interactions between estragole and methyleugenol 1′-hydroxylation and between estragole and safrole 1′-hydroxylation are to be expected because of the involvement of, respectively, P450 1A2 and P450 2A6 in the bioactivation of these compounds. Furthermore, poor metabolizer phenotypes in P450 2A6 might diminish the chances on bioactivation of estragole and safrole, whereas lifestyle factors increasing P450 1A2 activities such as cigarette smoking and consumption of charbroiled food might increase those chances for estragole and methyleugenol. © 2007 American Chemical Society.