The mammalian CYP1A1, CYP1A2, and CYP1B1 genes (encoding cytochromes P450 1A1, 1A2, and 1B1, respectively) are regulated by the aromatic hydrocarbon receptor (AHR). The CYP1 enzymes are responsible for both metabolically activating and detoxifying numerous polycyclic aromatic hydrocarbons (PAHs) and aromatic amines present in combustion products. Many substrates for CYP1 enzymes are AHR ligands. Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines. Variability in the human AHR affinity exists, but differences in human risk of toxicity or cancer related to AHR activation remain unproven. Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation. Intact animal data contradict pharmaceutical company policies that routinely test drugs under development; if a candidate drug shows CYP1 inducibility, further testing is generally discontinued for fear of possible toxic or carcinogenic effects. In the future, use of "humanized" mouse lines, containing a human AHR or CYP1 allele in place of the orthologous mouse gene, is one likely approach to show that the AHR and the CYP1 enzymes in human behave similarly to that in mouse.Classical cancer studies in the 1930s showed that coal tar applied to a rabbit's ear causes papillomas followed by tumors. The active ingredients in coal tar were determined to be polycyclic aromatic hydrocarbons (PAHs) 1 such as benzo [a]pyrene (BaP). The parent PAH at first was thought to be the carcinogen and an enzyme that metabolized PAHs thought to be beneficial in detoxification (1). It was subsequently shown that PAHs, metabolized to reactive intermediates, bind covalently to nucleic acids and proteins to form adducts (2); thus, the concept of "metabolic activation" by PAH-metabolizing enzymes was born.Mammalian cell cultures were found to have BaP hydroxylase (aryl hydrocarbon hydroxylase) activity that becomes highly induced within 12-24 h upon exposure to various PAHs (3). This paradigm for studying the response of cultured cells to PAH treatment has led to a wealth of knowledge concerning transcription, translation, and signal transduction pathways (4 -6).Some inbred mouse strains are "sensitive" to the PAH inducer, whereas others are not (7). Breeding sensitive C57BL/6 (B6) with resistant DBA/2 (D2) mice revealed that resistance was inherited largely as an autosomal recessive trait (8). When 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) was realized to be at least 30,000 times more potent than PAHs as an inducer of BaP hydroxylase, B6 and D2 mice were treated with dioxin, and the effective dose for 50% induction (ED 50 ) was shifted ϳ15-fold to the right in the ...

Conventional biochemical and molecular techniques identified previously several genes whose expression is regulated by the aryl hydrocarbon receptor (AHR). We sought to map the complete spectrum of AHR-dependent genes in male adult liver using expression arrays to contrast mRNA profiles in Ahr-null mice (Ahr Ϫ/Ϫ ) with those in mice with wild-type AHR (Ahr ϩ/ϩ ). Transcript profiles were determined both in untreated mice and in mice treated 19 h earlier with 1000 g/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Expression of 456 ProbeSets was significantly altered by TCDD in an AHR-dependent manner, including members of the classic AHRE-I gene battery, such as Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1. In the absence of exogenous ligand, AHR status alone affected expression of 392 ProbeSets, suggesting that the AHR has multiple functions in normal physiology. In Ahr Ϫ/Ϫ mice, only 32 ProbeSets exhibited responses to TCDD, indicating that the AHR is required for virtually all transcriptional responses to dioxin exposure in liver. The flavin-containing monooxygenases, Fmo2 and Fmo3, considered previously to be uninducible, were highly induced by TCDD in an AHR-dependent manner. The estrogen receptor ␣ as well as two estrogen-receptor-related genes (␣ and ␥) exhibit AHR-dependent expression, thereby extending cross-talk opportunities between the intensively studied AHR and estrogen receptor pathways. p53 binding sites are over-represented in genes down-regulated by TCDD, suggesting that TCDD inhibits p53 transcriptional activity. Overall, our study identifies a wide range of genes that depend on the AHR, either for constitutive expression or for response to TCDD.Initial studies of the aryl hydrocarbon receptor (AHR) focused on its roles in regulating the induction of CYP1 enzymes (Nebert et al., 2004) and mediating toxicity of dioxinlike chemicals (Okey et al., 2005). More recently, the creation of mice with altered AHR signaling revealed phenotypic changes that implicate the AHR in multiple aspects of growth, development, differentiation, and physiology, irrespective of exposure to toxic environmental chemicals (Fernandez-Salguero et al., 1995;Lahvis et al., 2000;Bunger et al., 2003; Walisser et al., 2004a,b). The AHR is a member of the basic helix-loop-helix PAS superfamily and is located in the cytoplasm in association with chaperone proteins such as heat shock protein 90 and XAP2. The AHR is activated by binding to TCDD, translocates to the nucleus, and dimerizes with another basic helix-loop-helix protein, ARNT. The activated AHR/ARNT heterodimer complex interacts with AHresponsive elements and activates the expression of AHR target genes (Nebert et al., 2004).Mice in which the Ahr gene has been knocked out (Ahr Ϫ/Ϫ ) are extraordinarily resistant to TCDD toxicity (Mimura et al., 1997;Peters et al., 1999;Bunger et al., 2003). Major toxic effects in mice such as hepatic toxicity, thymic atrophy, and cleft palate formation (Bunger et al., 2003) require that the AHR have an intact nuclear translocation/transactiva...

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The science of toxicology is devoted, in large part, to understanding mechanisms of toxicity so that we can more accurately assess the risk posed by exposure to xenobiotic agents and, perhaps, intervene in the toxicologic process to mitigate harm. Dioxin-like chemicals continue to be of great concern as environmental toxicants. About 30 years ago the aryl hydrocarbon receptor (AHR) was discovered as a specific binding site for 2,3,7,8-tetrachlorodibenzo-p-dioxin. This giant step led to our current view that essentially all toxic effects of dioxins are AHR-mediated. The AHR serves as the archetype for understanding toxicity mediated by other soluble receptors. The fact that toxicity is receptor-mediated has important implications, especially for dose-response relationships. In laboratory animals genetic differences in AHR gene structure lead to profound differences in responsiveness to dioxin-like chemicals. Humans, however, exhibit relatively few AHR polymorphisms and these seem to exert only modest effects on downstream events. Dioxin toxicity is fundamentally due to AHR-mediated dysregulation of gene expression. Our current challenging goal is to determine which dysregulated genes underlie specific forms of dioxin toxicity. Mapping AHR-mediated gene expression in a variety of biological systems may help explain why dramatic differences in susceptibility to dioxin toxicity exist among laboratory species and why humans appear to be relatively resistant to adverse effects of dioxins.

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