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J.Health Sci., 50(1), 82-85, 2004
CYP2D6-Mediated Mexiletine-Protein Adduct Formation
Yoshiro Saito,*, a, b Mayumi
Saeki,b Keiko
Maekawa,a, b Akiko
Hachisuka,a Reiko
Teshima,a Shogo
Ozawa,b, c
and Jun-ichi Sawadaa, b
aDivision of Biochemistry and Immunochemistry,
bProject Team for Pharmacogenetics, and
cDivision of Pharmacology,
National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
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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