VARIABILITY OF COUMARIN 7-HYDROXYLATION AND 3-HYDROXYLATION IN A JORDANIAN POPULATION IS SUGGESTIVE OF A FUNCTIONAL POLYMORPHISM IN CYTOCHROME-P450 CYP2A6

Objective: To determine the variability of coumarin 7- and 3-hydroxyla tion in a human population and to evaluate the evidence for the existe nce of genetic polymorphism in these pathways. 7-Hydroxylation of coum arin is considered to be a detoxication pathway, whilst 3-hydroxylatio n, which predominates in rats, leads to hepatotoxicity in the rat. Cou marin metabolic phenotypes could aid in refining the risk evaluation f or humans of dietary and environmental exposure to coumarin and for th e chronic use of coumarin in high doses as a drug to treat lymphoedema and certain cancers. Methods: Healthy male and female Jordanian volun teers (n = 103) were administered 2 mg coumarin by mouth and collected their 0-8-h urines. These, together with pre-dose blank urines, were analysed by selected-ion monitoring gas chromatography mass spectromet ry for their content of the coumarin metabolites 7-hydroxycoumarin (7O HC) and 2-hydroxyphenylacetic acid (2OHPAA), the latter arising from t he 3-hydroxylation pathway. Results: After coumarin administration, ex cretion of both 7OHC and 2OHPAA was highly variable. A coumarin metabo lic ratio (2OHPAA/7OHC) was suggestive of polymorphism. At least one s ubject had a metabolic response similar to an individual known to be b oth phenotypically and genotypically (CYP2A6 gene) 7-hydroxylation-def icient. Conclusion: In the light of the finding of high variability an d possible polymorphism in both the 7- and 3-hydroxylation of coumarin in a human population, we recommend a reappraisal of the risk evaluat ion of human exposure to coumarin, particularly in pharmaceutical dose s.