Metabolism of carcinogenic alpha-asarone by human cytochrome P450 enzymes

Major metabolites of alpha-asarone in liver microsomes are epoxide-derived side-chain diols. The intermediately formed epoxides are mutagenic and form DNA adducts and thus are likely responsible for the (hepato) carcinogenic effect of alpha-asarone observed in male mice. We here investigated the rol...

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Bibliographic Details
Published in:Naunyn-Schmiedeberg's archives of pharmacology 2020-02, Vol.393 (2), p.213-223
Main Authors: Cartus, Alexander T., Schrenk, Dieter
Format: Article
Language:English
Subjects:
Adducts
Anisoles - metabolism
Asarones
Biomedical and Life Sciences
Biomedicine
Carcinogens - metabolism
Cytochrome
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Demethylation
DNA adducts
Enzymes
Epoxidation
Epoxides
Humans
Hydroxylation
Liver
Metabolic activation
Metabolic rate
Metabolism
Metabolites
Microsomes
Microsomes, Liver - metabolism
Neurosciences
Original Article
Pharmacology/Toxicology
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Summary:Major metabolites of alpha-asarone in liver microsomes are epoxide-derived side-chain diols. The intermediately formed epoxides are mutagenic and form DNA adducts and thus are likely responsible for the (hepato) carcinogenic effect of alpha-asarone observed in male mice. We here investigated the role of eight human cytochrome P450 enzymes (CYP1A1, 1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4) in the metabolism of alpha-asarone using Supersomes™. The epoxidation of the side-chain of alpha-asarone was mainly catalyzed by CYP3A4 and to a lesser extent by 2B6 and 1A1 whereas the hydroxylation of the side-chain leading to ( E )-3′-hydroxyasarone was catalyzed by all investigated CYPs excluding CYP2A6. O -demethylation was catalyzed by CYP1A1, 2A6, 2B6, and 2C19. Applying relative activity factors (RAF) to the observed formation rates revealed that CYP3A4, at least at lower substrate concentrations, is nearly solely responsible for the formation of the mutagenic side-chain epoxides of alpha-asarone. Comparison of the RAF-corrected formation rates of all metabolites with those found in incubation with human liver microsomes revealed that the side-chain hydroxylation and epoxidation can be explained in good approximation by the tested hepatic CYPs, whereas other CYPs or enzymes may contribute to the O -demethylation of alpha-asarone. Therefore, the capacity for metabolic activation of alpha-asarone has to be expected to be widely present among the general population.
ISSN:0028-1298
1432-1912
DOI:10.1007/s00210-019-01724-0