Drug-induced liver injury has been associated with the generation of reactive metabolites, which are primarily detoxified via
glutathione conjugation. In this study, it was hypothesized that molecules involved in the synthesis of
glutathione would be diminished to replenish the
glutathione depleted through conjugation reactions. Since
S-adenosylmethionine (SAMe) is the primary source of the
sulfur atom in
glutathione, UPLC/MS and NMR were used to evaluate metabolites involved with the transulfuration pathway in urine samples collected during studies of eight liver toxic compounds in Sprague-Dawley rats. Urinary levels of
creatine were increased on day 1 or day 2 in 8 high dose liver toxicity studies.
Taurine concentration in urine was increased in only 3 of 8 liver toxicity studies while SAMe was found to be reduced in 4 of 5 liver toxicity studies. To further validate the results from the metabonomic studies, microarray data from rat liver samples following treatment with
acetaminophen was obtained from the Gene Expression Omnibus (GEO) database. Some genes involved in the trans-sulfuration pathway, including
guanidinoacetate N-methyltransferase,
glycine N-methyltransferase,
betaine-homocysteine methyltransferase and
cysteine dioxygenase were found to be significantly decreased while
methionine adenosyl
transferase II, alpha increased at 24 h post-dosing, which is consistent with the SAMe and
creatine findings. The metabolic and transcriptomic results show that the trans-sulfuration pathway from SAMe to
glutathione was disturbed due to the administration of heptatotoxicants.