INHIBITION OF MICROSOMAL OXIDATION OF ETHANOL BY PYRAZOLE AND 4-METHYLPYRAZOLE INVITRO - INCREASED EFFECTIVENESS AFTER INDUCTION BY PYRAZOLE AND 4-METHYLPYRAZOLE
INHIBITION OF MICROSOMAL OXIDATION OF ETHANOL BY PYRAZOLE AND 4-METHYLPYRAZOLE INVITRO - INCREASED EFFECTIVENESS AFTER INDUCTION BY PYRAZOLE AND 4-METHYLPYRAZOLE
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DOI：
10.1042/bj2390671
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发表时间：
1986-11-01
影响因子：
4.1
通讯作者：
CEDERBAUM, AI
中科院分区：
文献类型：
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作者：
FEIERMAN, DE;CEDERBAUM, AI
乙醇脱氢酶抑制剂吡唑和4-甲基吡唑也被发现是肝微粒体（微粒体组分）体外氧化乙醇的有效抑制剂。先前用吡唑或4-甲基吡唑处理2或3天的大鼠微粒体的乙醇氧化似乎对吡唑或4-甲基吡唑的体外抑制特别敏感。所有微粒体制剂中吡唑或4-甲基吡唑的抑制动力学混合，因为乙醇的Km升高，而Vmax降低。然而，吡唑（约0.35 mM），尤其是4-甲基吡唑（约0.03-0.10 mM）的Ki值远低于盐水对照（约0.7-1.1 mM）。相比之下，二甲基亚砜作为微粒体乙醇氧化抑制剂的Ki值在所有微粒体制剂中相似。吡唑和4-甲基吡唑与微粒体反应产生II型光谱变化，其幅度在吡唑或4-甲基吡唑处理后增加。因此，吡唑和4-甲基吡唑的抑制有效性增加似乎与这些化合物诱导的与细胞色素P-450同工酶的相互作用增加有关。这些同工酶具有与慢性乙醇处理诱导的同工酶相似的性质。因此，在使用吡唑或4-甲基吡唑评估乙醇代谢途径时需要谨慎，尤其是在长期乙醇处理后，因为这些药物除了抑制乙醇脱氢酶外，也是微粒体乙醇氧化的有效抑制剂。
Pyrazole and 4-methylpyrazole, which are inhibitors of alcohol dehydrogenase were also found to be effective inhibitors of the oxidation of ethanol by liver microsomes (microsomal fractions) in vitro. Ethanol oxidation by microsomes from rats previously treated for 2 or 3 days with either pyrazole or 4-methylpyrazole appeared to be especially sensitive to inhibition in vitro by pyrazole or 4-methylpyrazole. The kinetics of inhibition by pyrazole or 4-methylpyrazole in all microsomal preparations were mixed, as the Km for ethanol was elevated while Vmax was lowered. However, Ki values for pyrazole (about 0.35 mM) and especially 4-methylpyrazole (about 0.03-0.10 mM) were much lower than those found with the saline controls (about 0.7-1.1 mM). In contrast, Ki values for dimethyl sulphoxide as an inhibitor of microsomal ethanol oxidation were similar in all microsomal preparations. Pyrazole and 4-methylpyrazole reacted with microsomes to produce type II spectral changes whose magnitude increased after treatment with either pyrazole or 4-methylpyrazole. Thus the increased inhibitory effectiveness of pyrazole and 4-methylpyrazole appears to be associated with increased interactions with the cytochrome P-450 isoenzyme(s) induced by these compounds. These isoenzymes have properties similar to those of the isoenzyme induced by chronic ethanol treatment. Therefore, caution is needed in the use of pyrazole or 4-methylpyrazole to assess pathways of ethanol metabolism, especially after chronic ethanol treatment, since these agents, besides inhibiting alcohol dehydrogenase, are also effective inhibitors of microsomal ethanol oxidation.