The effect of spironolactone treatment on the cytochrome P450-mediated metabolism of the pyrrolizidine alkaloid senecionine by hepatic microsomes from rats and guinea pigs.
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.
Chung
W G
WG
Toxicology Program, Oregon State University, Corvallis 97331.
Buhler
D R
DR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D016686:Monocrotaline / Q000031:analogs & derivatives / Q000096:biosynthesis; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013148:Spironolactone / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; D011763:Pyrrolizidine Alkaloids; D013148:Spironolactone; D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; C009237:senecionine; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C007241:dehydroretronecine