Cytochrome P450 1A1 (CYP1A1) inhibitor alpha-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats: possible involvement of UGT-P450 interactions.
Cytochrome P450 1A1 (CYP1A1) inhibitor alpha-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats: possible involvement of UGT-P450 interactions.
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DOI：
10.1248/bpb.27.56
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发表时间：
2004
影响因子：
2
通讯作者：
K. Taura;Eri Naito;Y. Ishii;M. Mori;K. Oguri;H. Yamada
中科院分区：
文献类型：
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作者：
K. Taura;Eri Naito;Y. Ishii;M. Mori;K. Oguri;H. Yamada
本文研究了细胞色素P450（P450）配体和微粒体透化对大鼠肝微粒体介导的3-羟基苯并（a）芘[3-OH-B（a）P]葡萄糖醛酸化的影响。虽然α-萘甲酮（NF）显著降低了3-甲基胆蒽（MC）处理大鼠的非透化微粒体的UDP-葡萄糖醛酸基转移酶（UGT）活性，但当使用透化微粒体时，该抑制剂几乎没有任何作用，因为预期该抑制剂易于接近UGT。动力学分析表明，α-NF的抑制作用是竞争性的。这些结果表明，参与3-OH-B（a）P葡萄糖醛酸化的UGT亚型通过依赖于MC处理大鼠微粒体膜完整性质的机制受到CYP 1A抑制剂的干扰。P450可能通过UGT和P450之间的相互作用作为UGT某些亚型的底物转运蛋白。
The effects of cytochrome P450 (P450, CYP) ligands and permeabilization of microsomes on 3-hydroxybenzo(a)pyrene [3-OH-B(a)P] glucuronidation mediated by rat hepatic microsomes were studied. While the UDP-glucuronosyltransferase (UGT) activity with non-permeabilized microsomes from 3-methylcholanthrene (MC)-treated rats was markedly reduced by alpha-naphthoflavone (NF), this inhibitor had hardly any effect when permeabilized microsomes were used in which the inhibitor was expected to have easy access to UGT. Kinetic analysis indicated that the inhibitory effect of alpha-NF is competitive. These results suggest that a UGT isoform(s) involved in 3-OH-B(a)P glucuronidation is interfered by a CYP1A inhibitor via a mechanism dependent on the intact nature of microsomal membranes in MC-treated rats. It is likely that P450 functions as a substrate transporter for some isoforms of UGT via possible interactions between UGT and P450.