M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury

Nathalie H. Urrunaga, Ravirajsinh N. Jadeja, Vikrant Rachakonda, Daniel Ahmad, Leon P. McLean, Kunrong Cheng, Vijay Shah, William S. Twaddell, Jean Pierre Raufman, Sandeep Khurana

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The role of muscarinic receptor subtypes in modulating acute liver injury is unknown. We detected M1 muscarinic receptor (M1R) expression in human and murine hepatocytes, and investigated the consequences of M1R deficiency on acute liver injury in vivo and inhibiting M1R activation on hepatocyte injury in vitro. Age-matched wild-type (WT) and M1R-deficient (Chrm1-/-) male mice were injected intraperitoneally with 200 mg/kg acetaminophen (APAP) and euthanized 0, 2, 4, 16, 24, and 36 h later. Biochemical and histological parameters indicated that liver injury peaked within 16 h after APAP treatment and resolved by 24 h. Compared to WT, M1R-deficient mice had reduced intrahepatic hemorrhage and hepatocyte necrosis, reflected by an attenuated rise in serum alanine aminotransferase levels. Livers of M1R-deficient mice showed reduced hepatocyte DNA fragmentation and attenuated expression of injury cytokines (Il-1α, Il-1β, Il-6, and Fasl). In all mice hepatic glutathione levels decreased after APAP injection, but they recovered more quickly in M1R-deficient mice. During the course of APAP-induced liver injury in M1R-deficient compared to WT mice, hepatic Nrf-2, Gclc, and Nqo1 expressions increased and nitrotyrosine generation decreased. APAP metabolic pathways were not altered by M1R deficiency; expression of hepatic Cyp2e1, Cyp1a2, Cyp3a11, Cyp3a13, Car, and Pxr was similar in Chrm1-/- and WT mice. Finally, treatment of murine AML12 hepatocytes with a novel M1R antagonist, VU0255035, attenuated H2O2-induced oxidative stress, prevented GSH depletion, and enhanced viability. We conclude that M1R modify hepatocyte responses to oxidative stress and that targeting M1R has therapeutic potential for toxic liver injury.

Original languageEnglish (US)
Pages (from-to)66-81
Number of pages16
JournalFree Radical Biology and Medicine
Volume78
DOIs
StatePublished - Jan 2015

Keywords

  • Acetaminophen
  • G protein-coupled receptors
  • Liver
  • Muscarinic receptors
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Urrunaga, N. H., Jadeja, R. N., Rachakonda, V., Ahmad, D., McLean, L. P., Cheng, K., Shah, V., Twaddell, W. S., Raufman, J. P., & Khurana, S. (2015). M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury. Free Radical Biology and Medicine, 78, 66-81. https://doi.org/10.1016/j.freeradbiomed.2014.09.032