Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by cytochrome P-450 enzymes in rat liver.
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)
Williams
D E
DE
Department of Food Science and Technology, Oregon State University, Corvallis 97331.
Reed
R L
RL
Kedzierski
B
B
Dannan
G A
GA
Guengerich
F P
FP
Buhler
D R
DR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015786:Cytochromes b5 / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology*; D008297:Male; D016686:Monocrotaline / Q000031:analogs & derivatives*; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D003907:Dexamethasone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; C009237:senecionine; C007241:dehydroretronecine