Human cytochrome p450 enzyme specificity for the bioactivation of estragole and related alkenylbenzenes.
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 alpha-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.
Jeurissen
Suzanne M F
SM
Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
Punt
Ans
A
Boersma
Marelle G
MG
Bogaards
Jan J P
JJ
Fiamegos
Yiannis C
YC
Schilter
Benoit
B
van Bladeren
Peter J
PJ
Cnubben
Nicole H P
NH
Rietjens
Ivonne M C M
IM
D000081248:Allylbenzene Derivatives; D000840:Anisoles / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005054:Eugenol / Q000031:analogs & derivatives / Q000378:metabolism; D005421:Flavoring Agents / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D012451:Safrole / Q000378:metabolism; D013379:Substrate Specificity
D000081248:Allylbenzene Derivatives; D000840:Anisoles; D004791:Enzyme Inhibitors; D005421:Flavoring Agents; C005223:methyleugenol; D005054:Eugenol; C014037:1'-hydroxyestragole; D003577:Cytochrome P-450 Enzyme System; C007633:estragole; D012451:Safrole