Species difference in enantioselectivity for the oxidation of propranolol by cytochrome P450 2D enzymes

Shizuo Narimatsu, Naoko Kobayashi, Yasuhiro Masubuchi, Toshiharu Horie, Tomohito Kakegawa, Hiroshi Kobayashi, James P. Hardwick, Frank J. Gonzalez, Noriaki Shimada, Shigeru Ohmori, Mitsukazu Kitada, Kazuo Asaoka, Hiroyuki Kataoka, Shigeo Yamamoto, Testuo Satoh

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Abstract

We examined and compared enantioselectivity in the oxidation of propranolol (PL) by liver microsomes from humans and Japanese monkeys (Macaca fuscata). PL was oxidized at the naphthalene ring to 4-hydroxypropranolol, 5- hydroxypropranolol and side chain N-desisopropylpropranolol by human liver microsomes with enantioselectivity of [R(+)>S(-)] in PL oxidation rates at substrate concentrations of 10 μM and 1 mM. In contrast, reversed enantioselectivity [R(+)<S(-)] in PL 5-hydroxylation and N-desalkylation rates at the same substrate concentrations was observed in monkey liver microsomes, although the selectivity was the same for PL 4-hydroxylation between the two species. All oxidation reactions of the PL enantiomers in human liver microsomes showed biphasic kinetics, i.e. the reactions could be expressed as the summation of a low-K(m) phase and a high-K(m) phase. Inhibition studies using antibodies and characterization of CYP2D6 enzymes expressed in insect cells or human lymphoblastoid cells indicated that the enantioselectivity of PL oxidation, especially the ring 4- and 5- hydroxylations reflected the properties of CYP2D6 in human liver microsomes. In monkey liver microsomes, all of the oxidation reactions of S(-)-PL showed biphasic kinetics, whereas ring 4- and 5-hydroxylations were monophasic and side chain N-desisopropylation was biphasic for R(+)-PL. Similarly, from the results of inhibition studies using antibodies and inhibitors of cytochrome P450 (P450), it appears that the reversed selectivity [R(+)<S(-)] of PL oxidation rates is catalyzed by CYP2D enzyme(s) in monkey liver at low substrate concentrations. These results indicate that different properties of P450s belonging to the 2D subfamily cause the reversed enantioselectivity between human and monkey liver microsomes. (C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish
Article number4205
Pages (from-to)73-90
Number of pages18
JournalChemico-Biological Interactions
Volume127
Issue number1
DOIs
Publication statusPublished - 2000

Keywords

  • CYP2D6
  • Enantioselectivity
  • Heterologous expression system
  • Human liver microsomes
  • Monkey liver microsomes
  • Propranolol

ASJC Scopus subject areas

  • Toxicology

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    Narimatsu, S., Kobayashi, N., Masubuchi, Y., Horie, T., Kakegawa, T., Kobayashi, H., Hardwick, J. P., Gonzalez, F. J., Shimada, N., Ohmori, S., Kitada, M., Asaoka, K., Kataoka, H., Yamamoto, S., & Satoh, T. (2000). Species difference in enantioselectivity for the oxidation of propranolol by cytochrome P450 2D enzymes. Chemico-Biological Interactions, 127(1), 73-90. [4205]. https://doi.org/10.1016/S0009-2797(00)00174-5