抄録
The mRNAs or proteins of CYP2D isoforms have been demonstrated to be expressed not only in liver but also in several extrahepatic tissues. However, the functions and properties of CYP2D isoforms in extrahepatic tissues have yet to be clarified. The tissue distributions and the catalytic properties of the isoforms give valuable insights into their physiological and pharmacological functions. In this study, the tissue distributions of four isoforms (CYP2D1/5, 2D2, 2D3 and 2D4/18) in rat CYP2D subfamily were investigated. The expression of CYP2D mRNA in twelve kinds of tissues was detected by RT-PCR. mRNA of CYP2D1/5 was expressed in all tissues except the brain. mRNAs of CYP2D2 and CYP2D3 were mainly expressed in liver, kidney and small intestine mucosa. In brain, only mRNA of CYP2D4/18 was expressed. Furthermore, we cloned four cDNAs (CYP2D1, 2D2, 2D3 and 2D4) belonging to the CYP2D subfamily. Expression plasmids carrying CYP2D cDNAs were transformed intoSaccharomyces cerevisiae. A catalytic study of these CYP2D isoforms was done with debrisoquine, bufuralol and lidocaine. CYP2D2 had the highest debrisoquine 4-hydroxylation activity. Both CYP2D3 and CYP2D2 exhibited high lidocaine 3-hydroxylation activity. The activity of CYP2D1 was relatively low toward the three substrates. These findings indicate that CYP2D2 and CYP2D3 play major roles in the metabolism of xenobiotics in rat liver, kidney and small intestine mucosa which are exposed to xenobiotics such as drugs, food components and environmental contamination and that it is possible that CYP2D4 has endogenous substrates other than dugs.
