Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Reaction Mechanism of Troleandomycin on the Activity of Human Liver Microsomal Cytochrome P450 3A4

인체 간 조직의 Cytochrome P450 3A4의 활성에 대한 Troleandomycin의 작용기전

  • 김복량 (원광대학교 의약자원연구센터) ;
  • 오현숙 (원광대학교 의약자원연구센터) ;
  • 김혜정 (원광대학교 의약자원연구센터)
  • Published : 1995.12.01
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Abstract

Incubation of aflatoxin $B_1$ $(AFB_1)$ with microsomes isolated from human liver number 110 yielded two metabolite peaks which were aflatoxin $Q_1$ $(AFQ_1)$ and $(AFB_1)$-exo-8, 9-epoxide (exo-epoxide) in high performance liquid chromatography. Production ratio of $AFQ_1$ to exo-epoxide was 2.43$\pm $0.04. Metabolism of $(AFB_1)$ to $(AFQ_1)$ and exo-epoxide was inhibited by troleandomycin in a same degree although troleandomycin was not activated as a mechanism-based inhibitor. The inhibitory effect was dependent upon either the incubation time with $(AFB_1)$ or the preincubation time before the addition of $(AFB_1)$. Incubation of troleandomycin and NADPH by the microsomes resulted in the formation of a cytochrome P 450 (P450)-metabollc intermediate (MI) complex and the level was approximately 80% of total P450 3A4 in the microsomes. This figure was similar to that of the inhibitory effect of troleandomycin on $AFB_1$ metabolism. Glutathione which was reported that it prevented the formation of MI complex in rat liver microsomes did not inhibit the formation of MI complex in human liver microsomes. These results suggested that the inhibitory effect of troleandomycin on $AFB_1$ metabolism is due to the formation of MI complex with P450 3A4. And the reaction mechanism of troleandomycin by human liver microsomes might be dlfferent from that one by rat liver microsomes.

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References

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