Cytochrome P450 enzymes involved in the enhancement of propranolol N-desisopropylation after repeated administration of propranolol in rats

Shizuo Narimatsu, Masayuki Mochida, Takahiro Matsumoto, Yasuhiro Masubuchi, Toshiharu Horie, Kiyoshi Nagata, Yoshihiko Funae, Arthur K. Cho, Tokuji Suzuki

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Abstract

Repeated oral administration of propranolol (PL, 100 mg/kg daily, for 5, 10 and 15 days) to male Wistar rats increased PL N-desisopropylase and decreased PL 4-,5- and 7-hydroxylase activities in liver microsomes. The increase was highest at the 10 day time point whereas the decrease was relatively constant over the 15 day treatment period. There were no significant changes in the total content of cytochromes P450 (450) or cytochrome b5, or in NADPH-cytochrome c reductase activity during the PL treatment. The enhanced N-desisopropylase activities were markedly inhibited by α-naphthoflavone (a P450-1A1/2 inhibitor), and moderately by triacetyloleandomycin (a P450-3A1/2 inhibitor) and diethyldithiocarbamate (a P450-2E1 inhibitor). Phenacetin O-deethylase activity, an index of P450-1A2, was significantly increased on day 5, 10 and 15 of the treatment, whereas p-nitrophenol hydroxylase activity was elevated on day 10 only. The PL N-desisopropylation showed a strong and significant correlation with phenacetin O-deethylation, and a weaker but significant correlation with p-nitrophenol hydroxylation. Immunoblot analysis revealed that a protein band corresponding to P450-1A2 was increased by PL pretreatment, and protein band corresponding to P450-3A tended to be increased slightly, but other protein band corresponding to the subfamily of P450-2B, -2C, or -2E was not changed. Pretreatment of rats with P450 inducers (β-naphthoflavone, phenobarbital, acetone and dexamethasone) increased PL N-dealkylase activity in liver microsomes. Furthermore, antibodies raised against P450-1A and -3A enzymes, suppressed PL N-desisopropylation in a concentration-dependent manner, but P450-2E antibody did not. Reconstitution studies showed that P450-1A1, -1A2, -2E1 and -3A2 exhibited catalytic activities for PL N-dealkylation. These results suggest that P450-1A2 is a major PL N-desisopropylase in the PL-treated rats, and P450-3A related enzyme(s) and P450-2E1 as a moderate or minor enzyme are also involved in PL N-dealkylation in native and PL-treated rats.

Original languageEnglish
Pages (from-to)207-224
Number of pages18
JournalChemico-Biological Interactions
Volume101
Issue number3
DOIs
Publication statusPublished - Sep 6 1996

Keywords

  • 4-Hydroxylation
  • Cytochrome P450-1A2
  • Enzyme induction
  • Enzyme inhibition
  • N-Desisopropylation
  • Propranolol

ASJC Scopus subject areas

  • Toxicology

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  • Cite this

    Narimatsu, S., Mochida, M., Matsumoto, T., Masubuchi, Y., Horie, T., Nagata, K., Funae, Y., Cho, A. K., & Suzuki, T. (1996). Cytochrome P450 enzymes involved in the enhancement of propranolol N-desisopropylation after repeated administration of propranolol in rats. Chemico-Biological Interactions, 101(3), 207-224. https://doi.org/10.1016/0009-2797(96)03726-X