Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver.
Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver.
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发表时间：
1989-07
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通讯作者：
David E. Williams;Ralph L. Reed;Bogdan Kedzierski;G. Dannan;F. Guengerich;Donald R. Buhler
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作者：
David E. Williams;Ralph L. Reed;Bogdan Kedzierski;G. Dannan;F. Guengerich;Donald R. Buhler
大鼠在吡咯里西啶生物碱senecietin的氧化方面显示出明显的性别差异，特别是在N-氧化方面。这种性别差异在地塞米松治疗后基本消除。这些观察结果表明，男性特异性细胞色素P-450 UT-A和P-450 PCN-E在这种吡咯里西啶生物碱的代谢中的潜在参与。复溶的大鼠P-450 UT-A显示出较高的N-氧化速率（15 nmol min-1 nmol P-450-1），几乎是雄性大鼠肝微粒体中观察到的转换数的3倍。相比之下，大鼠P-450 UT-A显示出对necine吡咯[+/-）-6，7-二氢-7-羟基-1-羟甲基-5H-吡咯嗪，DHP）形成的活性低得多（1.0 nmol min-1 nmol P-450-1）。大鼠细胞色素P-450 PB-B和P-450 BNF-B对衰老的N-氧合和吡咯形成活性较低，速率小于1 nmol min-1 nmol P-450-1。兔抗大鼠P-450 UT-A抗体抑制未处理雄性大鼠肝微粒体的千里光碱-N-氧化活性达60%，对DHP产生的抑制较小。兔抗人P-450 NF（大鼠P-450 PCN-E的人同源物）抗体是未处理雄性大鼠肝微粒体产生DHP的有效抑制剂。用地塞米松预处理大鼠的微粒体，抗P-450 NF平行抑制DHP和N-氧化物的产生。我们认为，P-450同工酶UT-A和PCN-E的特异性可能是导致千里光N-氧化的性别差异较大的原因。（250字处删节）
Rats display a marked sex difference in the oxidation of the pyrrolizidine alkaloid senecionine, especially with respect to N-oxidation. This sex difference was largely eliminated following treatment with dexamethasone. These observations suggested the potential involvement of the male-specific cytochrome P-450 UT-A and the P-450 PCN-E in the metabolism of this pyrrolizidine alkaloid. Reconstituted rat P-450 UT-A exhibited a high rate of N-oxidation (15 nmol min-1 nmol P-450-1) which is almost 3-fold higher than the turnover number observed with male rat liver microsomes. In contrast, rat P-450 UT-A displayed a much lower activity toward necine pyrrole [+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine, DHP) formation (1.0 nmol min-1 nmol P-450-1). The N-oxygenation and pyrrole formation activities displayed by rat cytochromes P-450 PB-B and P-450 BNF-B toward senecionine were low, with rates less than 1 nmol min-1 nmol P-450-1. Rabbit antibody to rat P-450 UT-A inhibited the senecionine-N-oxidation activity of untreated male rat liver microsomes by 60%, with lesser inhibition of DHP production. Rabbit antibody to human P-450NF (the human homologue to rat P-450 PCN-E) was a potent inhibitor of DHP production by untreated male rat liver microsomes. With microsomes from dexamethasone-pretreated rats, anti-P-450NF inhibited DHP and N-oxide production in parallel. We conclude that the large sex difference in senecionine N-oxidation probably is the result of the specificity of P-450 isozymes UT-A and PCN-E.(ABSTRACT TRUNCATED AT 250 WORDS)