Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 63, Issue -, Pages 369-380Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.05.028
Keywords
Bioenergetics; Drug metabolism; Redox biology; Thioredoxin reductase
Funding
- U.S. NCI
- U.S. NIA
- Karolinska Institutet
- Swedish Research Council (Medicine)
- Swedish Cancer Society
- NSF-REU
- MSU IID Department
- NIH-CoBRE grant
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Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoguinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage. (C) 2013 Elsevier Inc. All rights reserved,
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