SPECIES-DIFFERENCES IN THE HEPATIC-MICROSOMAL ENZYME METABOLISM OF THE PYRROLIZIDINE ALKALOIDS

Species differences in pyrrolic metabolites and senecionine (SN) N-oxi de formation among eight animal species (sheep, cattle, gerbils, rabbi ts: hamsters, Japanese quail, chickens, rats) varying in susceptibilit y to pyrrolizidine alkaloid (PA) intoxication were measured in vitro b y hepatic microsomal incubations. The results suggested that there is not a strong correlation between the production of pyrrolic metabolite s and susceptibility of animals to PA toxicity. The rate of PA activat ion in hamsters, a resistant species, measured by formation of 7-dihyd ro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) far exceeded the rat e of SN N-oxide formation (detoxification) (DHP/N-oxide = 2.29). In co ntrast, SN N-oxide was the major metabolite in sheep, another resistan t species, with much lower production of DHP (DHP/N-oxide = 0.26). The roles of cytochrome P450s and flavin-containing monooxygenases (FMO) in bioactivation and detoxification of pyrrolizidine alkaloids (PA) we re studied in vitro using sheep and hamster hepatic microsomes. Chemic al and immunochemical inhibition data suggested that the conversion of SN to DHP is catalyzed mainly by cytochrome P450s (68-82%), whereas t he formation of SN N-oxide is carried out largely by FMO (55-71%). The re also appeared to be a high rate of glutathione-DHP conjugation in h amster (63%) and sheep (79%) liver microsomal incubation mixtures. The refore, low rates of pyrrole metabolite production coupled with glutat hione conjugation in sheep may explain the resistance of sheep to SN, whereas the high rate of GSH-DHP conjugation may be one of the factors contributing to the resistance of hamsters to intoxication by this PA . (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.