Oxidation of Optically Active Substrates by Human and Rat CYP2D Enzymes.

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  • NARIMATSU Shizuo
    Laboratories of Health Chemistry, Faculty of Pharmaceutical Sciences, Okayama University
  • YAMAMOTO Shigeo
    Biomolecular Sciences, Faculty of Pharmaceutical Sciences, Okayama University

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  • ヒトおよびラットＣＹＰ２Ｄ酵素による光学活性基質の酸化反応

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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 β-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.

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