摘要：An antiarrhythmic drug mexiletine, which is metabolized by CYP2D6 and, to a lesser extent, by CYP1A2, is known to sometimes induce allergic reactions. Since mexiletine itself is chemically inert, metabolic activation of the drug, required for the formation of protein adduct, is thought to be a first step in the induction of the allergic reactions. In the present study, we screened several cytochrome P450 (CYP) enzymes for their ability to form protein adducts with mexiletine. Of the 10 CYPs examined (CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5), CYP2D6 was most efficient in adduct formation with microsomal proteins. On autoradiographs of SDS-PAGE-separated proteins, a 52 kDa band was detected in the CYP2D6-expressing microsomes. These results suggest that the mexiletine-protein adduct is formed mainly by CYP2D6-dependent metabolic activation.
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