Evaluations of the trans-sulfuration pathway in multiple liver toxicity studies

Journal Article · Sun Feb 15 04:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.11.015· OSTI ID:21182728

Minjun, Chen ^[1]; Sun, Jinchun; Holland, Ricky D; Dragan, Yvonne; Weida, Tong ^[2]; Welsh, William ^[1]; Beger, Richard D ^[2]

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1. Environmental Bioinformatics Computational Toxicology Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States)
2. Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration, FDA, Jefferson, AR 72079 (United States)

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.

• OSTI ID: 21182728
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 235; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BETAINE
CREATINE
CYSTEINE
GLUTATHIONE
GLYCINE
HOMOCYSTEINE
LIVER
METABOLITES
METHIONINE
NUCLEAR MAGNETIC RESONANCE
RATS
TAURINE
TOXICITY
URINE