A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor.

CYP1A2 CYP3A4型 胺碘酮 微粒体 CYP2C8 细胞色素P450 酮康唑 内科学 内分泌学 CYP3A型 微粒体 同工酶 生物 化学 药理学 新陈代谢 生物化学 医学 抗真菌 微生物学 心房颤动
作者
Katsuhiro Ohyama,Miki Nakajima,Sumika Nakamura,Noriaki Shimada,Hiroshi Yamazaki,Tsuyoshi Yokoi
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期刊:PubMed 卷期号:28 (11): 1303-10 被引量:89
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Human cytochrome P450 (CYP) isoforms involved in amiodarone N-deethylation were identified, and the relative contributions of these CYP isoforms were evaluated in different human liver microsomes. The mean K(M) and V(max) values of amiodarone N-deethylation in microsomes from six human livers were 31.6 +/- 7.5 microM and 1.2 +/- 0.7 pmol/min/pmol of CYP, respectively. Ketoconazole and anti-CYP3A antibodies strongly inhibited amiodarone N-deethylase activity in human liver microsomes at a substrate concentration of 50 microM. Of 15 recombinant human CYP enzymes (19 preparations), CYP1A1, CYP3A4, CYP1A2, CYP2D6, CYP2C8, and CYP2C19 catalyzed amiodarone N-deethylation. The amiodarone N-deethylase activity at a substrate concentration of 5 microM was significantly correlated with the paclitaxel 6alpha-hydroxylase activity (r = 0.84, P <.05) in the human liver microsomes, whereas the amiodarone N-deethylase activity at 100 microM was significantly correlated with the testosterone 6beta-hydroxylase activity (r = 0.94, P <.005). According to the concept of relative activity factor, it was clarified that CYP2C8 as well as CYP3A4 were significantly involved in amiodarone N-deethylation in human livers at clinically significant concentrations and that the contributions of CYP1A2, CYP2C19, and CYP2D6 were relatively minor. However, there was a large interindividual variability in the contribution of each CYP isoform to amiodarone N-deethylase activity in human liver; the relevance of these enzymes would be dependent on the content of the respective isoforms and on the amiodarone concentration in the liver.

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