title: Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression.
abstract: The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC.
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.
authors.forename: Sathidpak
authors.initials: S
authors.lastname: Nantasanti
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.
authors.forename: Mathilda J M
authors.initials: MJ
authors.lastname: Toussaint
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.
authors.forename: Sameh A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.
authors.forename: Peter C J
authors.initials: PC
authors.lastname: Tooten
authors.affiliation: Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584CL, Utrecht, the Netherlands.|Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, University of Groningen, 9713 AV, Groningen, the Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000378:metabolism; D011725:Pyridines / Q000493:pharmacokinetics* / Q000633:toxicity; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins
chemical_list: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D011524:Protoporphyrins; D011725:Pyridines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins