Thursday, July 20, 2017
Drachman Hall, Room A112
DR. QING-YU ZHANG
Associate Professor, Department of Environmental Health Sciences, School of Public Health, University at Albany
"FUNCTION AND REGULATION OF INTESTINAL P450 ENZYMES"
The mammalian intestine provides the first site for metabolism of ingested xenobiotics, including therapeutic drugs, pollutants, and chemical carcinogens. These metabolic functions are performed by a variety of biotransformation enzymes, including the cytochrome P450 superfamily of monooxygenases. The intestine expresses many P450 genes, which can be regulated by many environmental or pathophysiological factors, including dietary components and tissue inflammation. Using an intestinal epithelium (IE)-specific Cpr-null (IECN) mouse model, it has been directly demonstrated that intestinal P450 enzymes play important roles in controlling the first-pass clearance, systemic bioavailability, and target tissue toxicity of many oral drugs and other xenobiotics. Intestinal P450s also metabolize numerous endogenous compounds, which may be important in the modulation of intestinal inflammation, immunity, and disease susceptibility. Furthermore, an inter-organ regulatory pathway was identified between liver and intestine, where a loss of hepatic CPR in the liver-specific Cpr-null (LCN) mice caused compensatory increases in intestinal P450 expression and capacity for first-pass metabolism of oral drugs. This inter-organ pathway appeared to involve reduced FXR activation and decreased expression of intestinal FGF15, an enterohepatic signaling molecule important in regulating bile acid homeostasis. These studies will ultimately lead to a better understanding of the environmental and genetic bases of interindividual differences in susceptibility to adverse drug reactions, and deliver new strategies for improvements in the treatment and prevention of intestinal diseases.
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