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Toxicol Sci. 2018 Dec 1;166(2):428-440. doi: 10.1093/toxsci/kfy206.

Cigarette Smoke Toxins-Induced Mitochondrial Dysfunction and Pancreatitis Involves Aryl Hydrocarbon Receptor Mediated Cyp1 Gene Expression: Protective Effects of Resveratrol.

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Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Department of Chemistry, Banwarilal Bhalotia College, Asansol, Ushagram, Asansol-713303, West Bengal, India.
Roche Molecular Systems, 1080, US-202, Branchburg, NJ 08876.
Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390.
GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426.
Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al-Ain, UAE.
Division of Gastroenterology, Departments of Medicine and Genetics, and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
National Cancer Institute, Center for Cancer Research, Bethesda, Maryland 20892.


We previously reported that mitochondrial CYP1 enzymes participate in the metabolism of polycyclic aromatic hydrocarbons and other carcinogens leading to mitochondrial dysfunction. In this study, using Cyp1b1-/-, Cyp1a1/1a2-/-, and Cyp1a1/1a2/1b1-/- mice, we observed that cigarette and environmental toxins, namely benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induce pancreatic mitochondrial respiratory dysfunction and pancreatitis. Our results suggest that aryl hydrocarbon receptor (AhR) activation and resultant mitochondrial dysfunction are associated with pancreatic pathology. BaP treatment markedly inhibits pancreatic mitochondrial oxygen consumption rate (OCR), ADP-dependent OCR, and also maximal respiration, in wild-type mice but not in Cyp1a1/1a2-/- and Cyp1a1/1a2/1b1-/- mice. In addition, both BaP and TCDD treatment markedly affected mitochondrial complex IV activity, in addition to causing marked reduction in mitochondrial DNA content. Interestingly, the AhR antagonist resveratrol, attenuated BaP-induced mitochondrial respiratory defects in the pancreas, and reversed pancreatitis, both histologically and biochemically in wild-type mice. These results reveal a novel role for AhR- and AhR-regulated CYP1 enzymes in eliciting mitochondrial dysfunction and cigarette toxin-mediated pancreatic pathology. We propose that increased mitochondrial respiratory dysfunction and oxidative stress are involved in polycyclic aromatic hydrocarbon associated pancreatitis. Resveratrol, a chemo preventive agent and AhR antagonist, and CH-223191, a potent and specific AhR inhibitor, confer protection against BaP-induced mitochondrial dysfunction and pancreatic pathology.

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