FOLATE-DEFICIENCY-INDUCED HOMOCYSTEINAEMIA IN RATS - DISRUPTION OF S-ADENOSYLMETHIONINES COORDINATE REGULATION OF HOMOCYSTEINE METABOLISM

In a recent hypothesis [Selhub and Miller (1992) Am. J. Clin. Nutr. 55 , 131-138], we proposed that homocysteinaemia arises from an interrupt ion in S-adenosylmethionine's (AdoMet) coordinate regulation of homocy steine metabolism The present study was undertaken to test a predictio n of this hypothesis, that homocysteinaemia due to folate deficiency r esults from impaired homocysteine remethylation due to the deficiency and impaired synthesis of AdoMet, with the consequent inability of thi s metabolite to function as an activator of homocysteine catabolism th rough cystathionine synthesis. Rats were made folate-deficient by feed ing them with a folate-free amino-acid-defined diet supplemented with succinyisulphathiazole. After 4 weeks, the deficient rats exhibited a 9.8-fold higher mean plasma homocysteine concentration and a 3.2-fold lower mean hepatic AdoMet concentration compared with folate-replete c ontrols. Subsequent supplementation for 3 weeks of the folate-deficien t rats with increasing levels of folate in the diet resulted in graded decreases in plasma homocysteine levels, accompanied by graded increa ses in hepatic AdoMet levels. Thus plasma homocysteine and hepatic Ado Met concentrations were inversely correlated as folate status was modi fied. In a second experiment, the elevation of plasma homocysteine in the deficient rats was found to be reversible within 3 days by intrape ritoneal injections of ethionine. This effect of ethionine is thought to be exerted through S-adenosylethionine, which is formed in the live r of these rats. Like AdoMet, S-adenosylethionine is an activator of c ystathionine beta-synthase and will effectively promote the catabolism of homocysteine through cystathionine synthesis. In crude liver homog enates of the rats treated with ethionine, cystathionine beta-synthase activity was 3-fold higher than that measured in homogenates from veh icle-treated controls.