The role of flavin-containing monooxygenase in the N-oxidation of the pyrrolizidine alkaloid senecionine.
The pyrrolizidine alkaloid, senecionine, is N-oxidized by purified pig liver flavin-containing monooxygenase but not by purified rabbit lung flavin-containing monooxygenase. The activity of the pig liver enzyme toward senecionine was linear with time and amount of enzyme. The oxygenation was not due to some indirect mechanism, such as O2- release from the enzyme, as scavengers of activated oxygen had no effect on product formation. The Km of purified pig liver flavin-containing monooxygenase for senecionine was 0.3 mM. Although senecionine is a substrate for the pig liver enzyme, studies performed with rat liver microsomes suggest that, in this species, cytochromes P-450 catalyze the majority of senecionine-N-oxidation. These experiments included inhibition by chemical inhibitors of P-450, treatment of the microsomes with elevated temperatures, inhibition by anti-NADPH-cytochrome P-450 reductase antibody, the effect of dexamethasone on N-oxidation, and relative amounts of flavin-containing monooxygenase determined by immunoquantitation. These results demonstrate that flavin-containing monooxygenase can be involved in the detoxication of pyrrolizidine alkaloids via N-oxidation, but the relative contribution of flavin-containing monooxygenase and cytochromes P-450 may be species and tissue dependent.
Williams
D E
DE
Department of Agricultural Chemistry, Oregon State University, Corvallis 97331.
Reed
R L
RL
Kedzierski
B
B
Ziegler
D M
DM
Buhler
D R
DR
D000818:Animals; D000906:Antibodies / Q000032:analysis; D000963:Antimetabolites / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005415:Flavins / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000276:immunology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine
D000906:Antibodies; D000963:Antimetabolites; D000972:Antineoplastic Agents, Phytogenic; D005415:Flavins; D011763:Pyrrolizidine Alkaloids; D003907:Dexamethasone; C009237:senecionine; D006899:Mixed Function Oxygenases