Beyond detoxification: Pleiotropic functions of multiple glutathione S-transferase isoforms protect mice against a toxic electrophile

Autoři: Kelsey A. Behrens aff001;  Leigh A. Jania aff002;  John N. Snouwaert aff002;  MyTrang Nguyen aff002;  Sheryl S. Moy aff003;  Andrey P. Tikunov aff004;  Jeffrey M. Macdonald aff004;  Beverly H. Koller aff001
Působiště autorů: Curriculum in Toxicology & Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff001;  Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff002;  Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff003;  Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225449


Environmental and endogenous electrophiles cause tissue damage through their high reactivity with endogenous nucleophiles such as DNA, proteins, and lipids. Protection against damage is mediated by glutathione (GSH) conjugation, which can occur spontaneously or be facilitated by the glutathione S-transferase (GST) enzymes. To determine the role of GST enzymes in protection against electrophiles as well as the role of specific GST families in mediating this protection, we exposed mutant mouse lines lacking the GSTP, GSTM, and/or GSTT enzyme families to the model electrophile acrylamide, a ubiquitous dietary contaminant known to cause adverse effects in humans. An analysis of urinary metabolites after acute acrylamide exposure identified the GSTM family as the primary mediator of GSH conjugation to acrylamide. However, surprisingly, mice lacking only this enzyme family did not show increased toxicity after an acute acrylamide exposure. Therefore, GSH conjugation is not the sole mechanism by which GSTs protect against the toxicity of this substrate. Given the prevalence of null GST polymorphisms in the human population (approximately 50% for GSTM1 and 20–50% for GSTT1), a substantial portion of the population may also have impaired acrylamide metabolism. However, our study also defines a role for GSTP and/or GSTT in protection against acrylamide mediated toxicity. Thus, while the canonical detoxification function of GSTs may be impaired in GSTM null individuals, disease risk secondary to acrylamide exposure may be mitigated through non-canonical pathways involving members of the GSTP and/or GSTT families.

Klíčová slova:

Enzyme metabolism – Enzymes – Spleen – Stomach – Toxicity – Urine – White blood cells – Glutathione chromatography


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