title: Flavin-containing monooxygenase: a major detoxifying enzyme for the pyrrolizidine alkaloid senecionine in guinea pig tissues.
abstract: Evidence based on optimal pH, thermal stability, and enzyme inhibition data suggests that the NADPH-dependent microsomal N-oxidation of the pyrrolizidine alkaloid senecionine is carried out largely by flavin-containing monooxygenase in guinea pig liver, lung, and kidney. In contrast, the hepatic microsomal conversion of senecionine to the pyrrole metabolite (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) is catalyzed largely by cytochrome P450. However, the rate of senecionine N-oxide formation (detoxication) far exceeded the rate of DHP formation (activation) in guinea pig liver microsomes over a range of pHs (pH 6.8 to 9.8). In guinea pig lung and kidney microsomes, N-oxide was the major metabolite formed from senecionine with little or no production of DHP. The high rate of detoxication coupled with the low level of activation of senecionine in liver, lung, and kidney may help explain the apparent resistance of the guinea pig to intoxication by senecionine and other pyrrolizidine alkaloids.
authors.affiliation: Department of Agricultural Chemistry, Oregon State University, Corvallis 97331.
authors.forename: C L
authors.initials: CL
authors.lastname: Miranda
authors.forename: W
authors.initials: W
authors.lastname: Chung
authors.forename: R E
authors.initials: RE
authors.lastname: Reed
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: M C
authors.initials: MC
authors.lastname: Henderson
authors.forename: J L
authors.initials: JL
authors.lastname: Wang
authors.forename: D E
authors.initials: DE
authors.lastname: Williams
authors.forename: D R
authors.initials: DR
authors.lastname: Buhler
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D008658:Inactivation, Metabolic; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology*; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009249:NADP / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010947:Plants, Toxic; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D012674:Senecio
chemical_list: D011763:Pyrrolizidine Alkaloids; D009249:NADP; C009237:senecionine; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase