Oxidation of Optically Active Substrates by Human and Rat CYP2D Enzymes.
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Accession number;00A0366741
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| Title;Oxidation of Optically Active Substrates by Human and Rat CYP2D Enzymes. |
| Author;
NARIMATSU SHIZUO
(Okayama Univ., Fac. of Pharm. Sci.)
YAMAMOTO SHIGEO
(Okayama Univ., Fac. of Pharm. Sci.)
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Journal Title;Xenobiotic Metabolism and Disposition
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Journal Code:X0758A
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ISSN:0916-1139
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VOL.15;NO.1;PAGE.39-45(2000)
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| Figure&Table&Reference;FIG.3, REF.14 |
| Pub. Country;Japan |
| Language;Japanese |
| Abstract;Human CYP2D6 is a causative enzyme in debrisoquine/sparteine-type genetic polymorphism, and is involved as a major enzyme in the oxidation of over 60 drugs that contain a nitrogen or sulfur atom in their chemical structures. Rats also have 6 kinds of CYP2D enzymes such as CYP2D1, CYP2D2, CYP2D3, CYP2D4, CYP2D5 and CYP2D18. Propranolol (PL), a typical .BETA.-adrenoceptor blocking agent, is a good substrate for human and rat liver microsomal fractions. Human liver microsomes catalyzed aromatic ring hydroxylations forming 4- and 5-hydroxypropranolols (4-and 5-OH-PLs), and side chain N-desisopropylation forming N-desisopropylpropranolol (NDP) . Rat liver microsomes catalyzed aromatic ring 7-hydroxylation in addition to the formation of the three metabolites. PL has an asymmetric carbon at the side chain, yielding R (+)-PL and S (-)-PL. Human liver microsomes showed substrate enantioselectivity of R (+)-PL > S (-)-PL for the formation of the three metabolites, whereas rat liver microsomes exhibited different selectivity: R (+)-PL < S (-) -PL for the formation of 4-OH-PL,5-OH-PL and NDP; R (+)-PL > S (-)-PL for the formation of 7-OH-PL. Possible mechanisms causing such a differential enantioselectivity in the oxidation of PL by CYP2D6 and CYP2D2 were discussed. (author abst.) |
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