Regulation of cytochrome P-450c by glucocorticoids and polycyclic aromatic hydrocarbons in cultured fetal rat hepatocytes |
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| Authors: | J M Mathis R A Prough R N Hines E Bresnick E R Simpson |
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| Affiliation: | 1. The Cecil H. and Ida Green Center for Reproductive Biology Sciences and Departments of Biochemistry and Obstetrics and Gynecology, University of Texas Health Science Center, Dallas, Texas 75235, U.S.A.;2. The Eppley Institute for Research in Cancer and Allied Diseases and Departments of Biochemistry and Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68105 U.S.A.;1. Department of Kinesiology and Physical Education, McGill University, 475 Pine Avenue West, Montreal, Quebec, H2W 1S4, Canada
;2. Feil & Oberfeld/CRIR Research Center, Jewish Rehabilitation Hospital, 3205 Alton, Goldbloom Place, Laval, Quebec, H7V 1R2, Canada;1. Yale University, Yale School of Management, United States;2. Northwestern University, Kellogg School of Management, Managerial Economics and Decision Sciences Department, United States;1. Yale School of Management, Yale University, United States;2. Department of Statistics and Operations Research, University of Santiago de Compostela, Spain;3. Toulouse School of Economics, Université Toulouse 1, France;1. Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, and Division of Epidemiology, Department of Health Research and Policy, School of Medicine, Stanford University, Stanford, California;2. Division of Epidemiology, Department of Public Health Sciences, School of Medicine, University of California–Davis, Davis, California;3. Department of Statistics, University of California–Irvine, Irvine, California;4. Medical Services, Veteran Affairs, Palo Alto Health Care System, Palo Alto, California |
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| Abstract: | The actions of polycyclic aromatic hydrocarbons and glucocorticoids to regulate the synthesis of cytochrome P-450c (the major isozyme induced by polycyclic aromatic hydrocarbons) were investigated in fetal rat hepatocytes maintained in primary monolayer culture. Treatment of hepatocytes in culture with 1,2-benzanthracene resulted in a 50-fold increase in 7-ethoxycoumarin O-deethylase activity. The level of P-450c increased in the cells in a time-dependent fashion as determined by immunoelectrophoretic analysis. The inductive effect of BA was potentiated approximately 1.6- to 2.3-fold when 1 microM dexamethasone was included in the culture medium. However, dexamethasone alone had little or no effect on the induction of P-450c. The rate of synthesis of P-450c was examined by immunoisolation of the specific isozyme from total cellular proteins radiolabeled with [35S]methionine and from the protein products formed during in vitro translation of the isolated mRNA. In addition, the amount of mRNA specific for cytochrome P-450c was determined by Northern blot analysis of RNA extracted from cultured cells. The changes in the rates of synthesis and mRNA levels were found to parallel the changes in enzyme activity. The concentration of dexamethasone required to cause a half-maximal increase in P-450c content in the presence of 1,2-benzanthracene was between 10(-8) and 10(-7) M. It is concluded that glucocorticoids act synergistically with polycyclic aromatic hydrocarbons to increase the levels of P-450c expressed in the fetal rat liver, and that this action is likely mediated by the classical type II glucocorticoid receptor. |
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