Chung W G, Buhler D R
Toxicology Program, Oregon State University, Corvallis 97331.
Toxicol Appl Pharmacol. 1994 Aug;127(2):314-9. doi: 10.1006/taap.1994.1167.
Spironolactone (SPL), a known inducer of cytochrome P4503A, was injected into rats and guinea pigs in order to investigate species differences in pyrrolizidine alkaloid (PA) metabolism. Liver microsomes from treated male rats showed an increased (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) formation of 47% from the PA senecionine, coincident with the induction of P4503A1, whereas senecionine N-oxidation was decreased by 49%, probably due to a reduction in hepatic P4502C11 concentrations. By contrast, liver microsomes from SPL-treated female rats exhibited almost a 500% increase in both DHP and senecionine N-oxide production, coincident with the marked induction of P4503A1. In guinea pigs of both sexes, oral treatment with SPL caused an approximately 50% increased formation of both DHP and senecionine N-oxide by liver microsomes. Only a slight increase in hepatic concentrations of P4503A1 occurred in the treated guinea pigs. SPL treatment increased testosterone 16 beta-hydroxylase activity by 100% in both sexes of guinea pigs. Use of the P4503A1 specific inhibitor triacetyloleandomycin showed that the P4503A sub-family played an important role in senecionine bioactivation in untreated or SPL-treated rats but not in both untreated and SPL-treated guinea pigs. This study demonstrated that P4503A was not the major enzyme for senecionine metabolism in guinea pigs.
为了研究吡咯里西啶生物碱（PA）代谢的种属差异，将已知的细胞色素P4503A诱导剂螺内酯（SPL）注射到大鼠和豚鼠体内。经处理的雄性大鼠肝脏微粒体中，PA千里光碱生成（±）-6,7-二氢-7-羟基-1-羟甲基-5H-吡咯嗪（DHP）的量增加了47%，这与P4503A1的诱导相一致，而千里光碱N-氧化作用降低了49%，这可能是由于肝脏中P4502C11浓度降低所致。相比之下，经SPL处理的雌性大鼠肝脏微粒体中，DHP和千里光碱N-氧化物的生成量均增加了近500%，这与P4503A1的显著诱导相一致。在两性豚鼠中，口服SPL导致肝脏微粒体生成DHP和千里光碱N-氧化物的量均增加约50%。在经处理的豚鼠中，肝脏中P4503A1的浓度仅略有增加。SPL处理使两性豚鼠的睾酮16β-羟化酶活性提高了100%。使用P4503A1特异性抑制剂三乙酰竹桃霉素表明，P4503A亚家族在未处理或经SPL处理的大鼠中，对千里光碱的生物活化起重要作用，但在未处理和经SPL处理的豚鼠中均不起作用。这项研究表明，P4503A不是豚鼠中千里光碱代谢的主要酶。
