Role of Aryl Hydrocarbon Receptor-mediated Induction of the CYP1 Enzymes in Environmental Toxicity and Cancer*
By D. Nebert, T. Dalton, A. Okey, F. Gonzalez. Journal of Biological Chemistry, 2004
1,173 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Health, Toxicology and Mutagenesis
View Paper: https://www.semanticscholar.org/paper/17e36fcd871026c2b05ac1dfd1d448e3d6c76bbb
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In Health, Toxicology and Mutagenesis
Citations in the corpus
- Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. (2011, neutral): “Considering the results of TCDD ligand-binding analysis of human placental samples which demonstrated that the relative affinity of the human AhR for TCDD can differ by more than 10-fold (Harper et al., 2002; Nebert et al., 2004), this variation in relative response may not be surprising.”
- Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans (2015, background): “receptor obtaining beneficial effects against cancer, as it is reported that the activation of this receptor may be involved in some types of tumors [91].”
- Polycyclic aromatic hydrocarbons: from metabolism to lung cancer. (2015, background): “Carcinogenic PAHs such as BaP or 3-methylcholanthrene are ligands of AhR (Nebert et al., 2004).”
- Elucidating mechanisms of drug-induced toxicity (2005, background): “In some cases, upregulation is detrimental, whereas in other cases it is beneficia”
- Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. (2013, background): “…xenobiotics which act as AhR ligands such as methylcholanthrene and other polycyclic aromatic hydrocarbons, dioxins, β-naphthoflavone (Table 3; Nebert et al., 2004), as well as atypical inducers including omeprazole and primaquine which regulate transcription through the same response…”
- Tobacco Smoking Leads to Extensive Genome-Wide Changes in DNA Methylation (2013, background): “Tobacco smoke is a remarkable source of polycyclic aromatic hydrocarbons (PAHs) that trigger the AHR signaling pathway [22–24], leading to several pathological effects in humans through AHR-dependent changes in gene expression [25–28].”