title: Marmoset cytochrome P450 2D8 in livers and small intestines metabolizes typical human P450 2D6 substrates, metoprolol, bufuralol and dextromethorphan.
abstract: 1. Although the New World non-human primate, the common marmoset (Callithrix jacchus), is a potentially useful animal model, comprehensive understanding of drug metabolizing enzymes is insufficient. 2. A cDNA encoding a novel cytochrome P450 (P450) 2D8 was identified in marmosets. The amino acid sequence deduced from P450 2D8 cDNA showed a high sequence identity (83-86%) with other primate P450 2Ds. Phylogenetic analysis showed that marmoset P450 2D8 was closely clustered with human P450 2D6, unlike P450 2Ds of miniature pig, dog, rabbit, guinea pig, mouse or rat. 3. Marmoset P450 2D8 mRNA was predominantly expressed in the liver and small intestine among the tissues types analyzed, whereas marmoset P450 2D6 mRNA was expressed predominantly in the liver where P450 2D protein was detected by immunoblotting. 4. By metabolic assays using marmoset P450 2D8 protein heterologously expressed in Escherichia coli, although P450 2D8 exhibits lower catalytic efficiency compared to marmoset and human P450 2D6 enzymes, P450 2D8 mediated O-demethylations of metoprolol and dextromethorphan and bufuralol 1'-hydroxylation. 5. These results suggest that marmoset P450 2D8 (also expressed in the extrahepatic tissues) has potential roles in drug metabolism in a similar manner to those of human and marmoset P450 2D6.
authors: a Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan .
authors: Shotaro
authors: S
authors: Uehara
authors: Yasuhiro
authors: Y
authors: Uno
authors: Yuya
authors: Y
authors: Hagihira
authors: Norie
authors: N
authors: Murayama
authors: Makiko
authors: M
authors: Shimizu
authors: Takashi
authors: T
authors: Inoue
authors: Erika
authors: E
authors: Sasaki
authors: Hiroshi
authors: H
authors: Yamazaki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002144:Callithrix / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D003915:Dextromethorphan / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D007438:Introns / Q000235:genetics; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008790:Metoprolol / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009928:Organ Specificity / Q000235:genetics; D010084:Oxidation-Reduction; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D018076:DNA, Complementary; D004983:Ethanolamines; D007527:Isoenzymes; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003915:Dextromethorphan; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol
keywords: CYP2D6; CYP2D8; Common marmoset; drug oxidation; human