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Andrew G. Smith,¹ Reginald Davies,¹ Timothy P. Dalton,² Marian L. Miller,² David Judah,¹ Joan Riley,¹ Timothy Gant,¹ and Daniel W. Nebert²

¹MRC Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, United Kingdom; ²Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

Abstract

Several forms of cytochrome P450 (CYP) appear to metabolize principally pharmaceutical agents, as well as other dietary and plant chemicals. Other CYP forms have major roles in steroid, sterol, and bile acid metabolism. CYP1A2 expression is constitutively high in mouse liver and is well known for metabolizing several drugs and many procarcinogens to reactive intermediates that can cause toxicity or cancer. CYP1A2 is also known to carry out several endogenous functions such as uroporphyrinogen and melatonin oxidation and the 2- and 4-hydroxylations of estradiol. We have used cDNA microarray analysis of the untreated Cyp1a2(-/-) knockout mouse to search for changes in gene expression that might indicate important intrinsic roles for this enzyme. For 15 of the up- or downregulated genes, these increases or decreases were corroborated by reverse-transcription real-time polymerase chain reaction. Other than upregulation of the Hprt gene (used in the selection procedure for disrupting the Cyp1a2 gene) , we found several genes upregulated that are associated with cell-cycle regulation and lipid metabolism. Besides Cyp1a2, the gene exhibiting the greatest downregulation was Igfbp1 (insulin-like growth factor binding protein-1) , showing only 12% expression of that in the Cyp1a2(+/+) wild-type liver. Recurrent themes between both up- and downregulated genes include cell-cycle control, insulin action, lipogenesis, and fatty acid and cholesterol biosynthetic pathways. Histologically, the Cyp1a2(-/-) mouse exhibited an approximately 50% decrease in lipid stored in hepatocytes, and 50% increase in lipid present in interstitial fat-storing cells compared with that in the Cyp1a2(+/+) wild-type. These data suggest that the CYP1A2 enzyme might perform additional hepatic endogenous functions heretofore not appreciated. Key words: cDNA expression library , cell cycle control , cholesterol biosynthesis , CYP1A2, endogenous substrate metabolism , CYP1A2, foreign chemical metabolism , Cyp1a2(-/-) knockout mouse , fatty acid biosynthesis , insulin action , lipogenesis. Environ Health Perspect 111:855-861 (2003) .