Evaluation of CYP2D6 protein expression and activity in the small intestine to determine its metabolic capability in the Japanese population

Abstract

CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the firstpass metabolism of orally administered drugs. Several CYP enßymes have been identified in the small intestine of Caucasians, but intestinal CYP enßymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6ß.ast;10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyßed using realtime RT-PCR and Western blotting, respectively. Bufuralol 1'-hydroxylation, a marker of CYP2D6 activity, was analyßed using HPLC. Frequencies of the CYP2D6ß.ast;1/ß.ast;1, ß.ast;1/ß.ast;10, and ß.ast;10/ß.ast;10 genotypes in the jejunal tissue were 29.0% (n=9), 35.5% (n=11), and 35.5% (n=11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism.