S37 Role of Cyp1 genes in Benzo[a]pyrene and Dioxin induced pancreatitis: Attenuation by Ahr Antagonists.

Narayan Avadhani , University of Pennsylvania, Philadelphia, PA
We have previously reported that Cyp1a1 and 1b1 proteins are bimodally targeted to the endoplasmic reticulum and mitochondria. The mitochondrial Cyps 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, benzo[a]pyrene (BaP) and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induce pancreatic mitochondrial respiratory dysfunction and also markers of pancreatitis. This effect is likely mediated by aryl hydrocarbon receptor (Ahr) mediated since pancreatic tissues from Cyp1 gene knock out mice were refractory to the xenobiotic effects and was also attenuated by Ahr antagonists CH-223191 and resveratrol. We show that BaP treatment markedly inhibits pancreatic mitochondrial oxygen consumption rate (OCR), ADP-dependent OCR, and also reserve OCR, in wild-type mice but not in Cyp1a1/1a2(–/–) and cyp1a1/1a2/1b1(-/-). Additionally, both BaP and TCDD treatment markedly affected mitochondrial complex IV activity, in addition to causing marked reduction in mitochondrial DNA contents. Interestingly, our results show that the Ahr antagonist resveratrol, attenuated BaP-induced mitochondrial defects in the pancreatic tissue, and reversed both the levels of secretion of biomarker α-amylase and inflammatory markers based on histopathology. The role of mitochondrial Cyp1b1 was ascertained using transgenic mice mostly expressing mitochondrial Cyp1b1 enzyme. We propose that increased mitochondrial respiratory dysfunction and oxidative stress mediated by mitochondrial metabolism of PAHs is associated with cigarette toxins induced pancreatitis which i9nvariably leads to pancreatic cancer. Resveratrol, a chemopreventive agent and Ahr antagonist render protection against BaP-induced pancreatic pathology. (Supported by NIH grant RO1 GM-34883 and an endowment from the Harriett Ellison Woodward trust).