CYP2A6 polymorphisms: is there a role for pharmacogenomics in preventing coumarin-induced hepatotoxicity in lymphedema patients?

Lymphedema is a chronic progressive and significantly disabling disease that affects over 150 million people worldwide. Coumarin is an effective pharmacological treatment, but is banned in some countries due to incidences of hepatotoxicity in rats and mice, and the rare finding of similar hepatotoxicity in humans. Cytochrome P450 (CYP)2A6 is the major enzyme involved in metabolizing coumarin to 7-hydroxycoumarin. A reduction in CYP2A6 activity will lead to shunting of coumarin into other metabolic pathways. In particular, coumarin is metabolized by CYP3A4 to form 3-hydroxycoumarin, the major metabolite in mice and rats. It has been shown that an increase in the 3-hydroxycoumarin ratio is associated with an increased production of the significant cytotoxic product o-hydroxyphenylacetylacetaldehyde (o-HPA), suggesting that a shunting of coumarin metabolism away from 7-hydroxylation is the cause of the toxicity. Hence, poor CYP2A6 metabolizers are more likely to metabolize coumarin via the cytotoxic pathway. Identifying these patients, and not treating them with coumarin, may reduce the incidence of toxicity associated with this drug. The technology to do so exists, but more information is required regarding the mechanism of coumarin toxicity.