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 enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes 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 CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using realtime RT-PCR and Western blotting, respectively. Bufuralol 1′-hydroxylation, a marker of CYP2D6 activity, was analyzed using HPLC. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*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. Key words CYP 2D6; small intestine; Japanese; polymorphism; bufuralol CYP enzymes are present in most tissues in the body, but are most abundant in the liver. There, they play a pivotal role in the metabolism of endogenous substrates and of exogenous compounds such as xenobiotics.1) Their presence in extrahepatic tissues, such as the esophagus, stomach, and small intestine, 2-4) also contributes to drug metabolism. 5-7) Paine et al. reported a significant contribution of CYP enzymes in the small intestine to the first-pass metabolism of midazolam, specifically by intestinal CYP3A4.7) Expressions of CYP3A, CYP2C9, CYP2C19, CYP2D6, CYP2J2, and CYP4F proteins have been demonstrated in the small intestine of Caucasians. 4,8) Of these, CYP2D6 plays a particularly important role in drug metabolism. Although CYP2D6 accounts for only 2% of the total CYP protein in the liver, it is a very important isoform because it metabolizes approximately 20-25% of commonly used drugs, including codeine, tramadol, and tamoxifen. 9) However, CYP2D6 expression and activity have not yet been characterized in the small intestine of the Japanese population.CYP2D6 gene polymorphisms are produced from over 109 allelic variants.10) The phenotypes resulting from these polymorphisms are associated with abolished, decreased, and increased enzyme activity, and the resulting phenotypes can be classified as a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultra-rapid metabolizer (UM), based ...

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