The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity Yukio Yamamoto, Takeshi Kawamoto, and Masahiko Negishi * Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA Received 7 June 2002, and in revised form 30 July 2002 Abstract The nuclear receptor CAR (constitutive active receptor) mediates the induction of transcription of cytochromeP450 (CYP) genes by phenobarbital (PB) and PB-type inducers. A recent study using CAR-null mice has shown that CAR regulates not only the CYP genes but also other genes encoding various drug/steroid-metabolizing enzymes. In addition to coordinating these enzymes, CAR plays other roles in hepatic gene expression: CAR represses various genes including carnitine palmitoyltransferase 1a and phos- phoenolpyruvate carboxykinase 1 in response to PB, and the receptor regulates the constitutive expression of genes such as squalene epoxidase. On the other hand, induction of certain genes such as aminolevulinatesynthase1 by PB is not regulated by CAR. Here we describe diverse roles of CAR in hepatic gene expression with a particular focus on endogenous substances such as cholesterol, bilirubin, and steroid hormones. Published by Elsevier Science (USA). Phenobarbital (PB) 1 has pleiotropic effects on various cellular processes in liver through altering the expression of a large number of hepatic genes, including induction of xenochemical-metabolizing enzymes such as CYPs and UDP–glucuronosyltransferase (UGT) [1,2]. Since its discovery in the early 1960s, PB induction of enzymes has been intensively investigated to understand the regulatory mechanisms. Therefore, it is not surprising to find that investigations have led us to identify a nuclear orphan receptor CAR as a PB-responsive transcription factor [3]. CAR, acting as a RXR heterodimer, binds to the PB-responsive enhancer module (PBREM) and ac- tivates gene transcription [4–6]. Recent studies have shown that the activation results in coordinate regula- tion of hepatic genes to counter chemical insults [7]. In addition to PB-type inducers, the receptor also responds to steroid hormones and their metabolites in in vivo and/or in vitro assays [8,9]. CAR is also implicated in the constitutive expression of hepatic genes [7]. We shall begin our short article by analyzing the genes that are regulated by CAR. For more details of the gene analysis readers should refer to our original paper [7], and for general roles of nuclear receptors in hepatic function to a recent review [10]. A recent cDNA microarray analysis of hepatic gene expression in wild-type and CAR-null mice revealed over 70 CAR-regulated genes that were either induced or repressed in response to PB treatment [7]. A group of the induced genes primarily consisted of xenochemical- metabolizing enzymes: for example, Cyp2b10, Cyp3a11, NADPH–cytochrome P450 reductase, flavin-containing monooxygenase 5, and aldehyde dehydrogenase 1. NADPH–cytochrome P450 reductase transfers electrons to reduce cytochrome P450 and often limits microsomal cytochrome P450-dependent monooxygenase activity. CAR appears to coordinate the induction of reductase with that of CYPs. PB induction of the aldehyde dehy- drogenase 1 (Aldh1) gene is also regulated by CAR. ALDHs catalyze oxidation of aldehydes and provide the major defense against aldehyde toxicity. ALDH 1 pref- erentially converts short-chain aldehydes to carboxylic acids, thereby protecting cells from toxicity of aldehydes Archives of Biochemistry and Biophysics 409 (2003) 207–211 www.elsevier.com/locate/yabbi ABB * Corresponding author. Fax: 1-919-541-0696. E-mail address: negishi@niehs.nih.gov (M. Negishi). 1 Abbreviations used: PB, Phenobarbital; CAR, constitutive active or androstane receptor; PXR, pregnane X receptor; FXR, farnesoid X- activated receptor; LXR, liver X receptor; RXR, retinoid X receptor. 0003-9861/02/$ - see front matter. Published by Elsevier Science (USA). PII:S0003-9861(02)00456-3