Microsomal formation of a pyrrolic alcohol glutathione conjugate of the pyrrolizidine alkaloid senecionine.
1. Pyrrolizidine alkaloids (PAs) are metabolized primarily to putative dehydroalkaloid (PA pyrrole) metabolites and to PA N-oxide by rat liver microsomal monooxygenases. 2. The dehydroalkaloids are highly reactive and either bind covalentely to tissue nucleophiles or are hydrolysed to the more stable pyrrole, (R,S)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), and the corresponding necic acid. 3. Addition of glutathione (GSH 1 mM) to incubation mixtures containing rat liver microsomes and the PA senecionine (SN), resulted in the formation of a conjugate of DHP with GSH. 5. The mass spectrum of this DHP-GSH conjugate was identical to that of the chemically-synthesized dehydroretronecine (the R enantiomer of the racemic DHP) and GSH. 6. Only negligible amounts of DHP-GSH conjugate were formed when DHP itself was incubated with GSH at physiological pH. 7. These findings provide strong evidence for the microsomal conversion of SN to a highly reactive metabolite, presumably dehydrosenecionine, which then reacts with GSH to form the DHP-GSH conjugate. 8. It is likely that a similar mechanism is responsible in vivo for the formation of GSH conjugates of DHP from SN and other PAs.
Reed
R L
RL
Department of Agricultural Chemistry, Oregon State University, Corvallis.
Miranda
C L
CL
Kedzierski
B
B
Henderson
M C
MC
Buhler
D R
DR
D000438:Alcohols / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000438:Alcohols; D000972:Antineoplastic Agents, Phytogenic; D011758:Pyrroles; D011763:Pyrrolizidine Alkaloids; C009237:senecionine; D005978:Glutathione