Cytochrome P1-450 is the form of P-450 most closely associated with polycyclic-hydrocarbon-induced aryl hydrocarbon hydrolase (AHH) activity. Chen et al. (1983) cloned a portion of the genomic gene. The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of many proteins including drug-metabolizing enzymes such as the cytochrome P-450 proteins. The P1-450 that is induced by TCDD is the same as AHH. Jaiswal et al. (1985) used a human cell line in which treatment with TCDD resulted in high levels of AHH (P1-450) activity and of human P1-450. Jaiswal et al. (1986) presented the complete amino acid sequence of cytochrome P1-450, consisting of 515 residues.

Quattrochi et al. (1985) cloned human P450DX genes and concluded that there are at least 2 in humans.

Jaiswal et al. (1985) and Kawajiri et al. (1986) isolated and analyzed the complete nucleotide sequence of a human genomic clone highly homologous to the rat cytochrome P-450 that is induced by methylcholanthrene and TCDD.

Kawajiri et al. (1986) constructed a fusion gene by ligating the 5-prime flanking region of the P-450c gene to the structural gene for prokaryotic chloramphenicol acetyltransferase (CAT), expressed the CAT activity in mouse cells in response to administered methylcholanthrene. Thus, the isolated human gene was indeed one for methylcholanthrene inducibility.

Jaiswal et al. (1985) estimated that the TCDD-inducible P-450 gene family diverged from the phenobarbital-inducible P-450 gene family (see 122720) more than 200 million years ago. Nebert and Gonzalez (1987) estimated that this divergence occurred more than 750 million years ago.

By analysis of the common 5-prime flanking region shared by CYP1A1 and CYP1A2, Corchero et al. (2001) demonstrated the presence of xenobiotic response elements (XREs) previously reported for CYP1A1 and CYP1A2 and several additional consensus sequences for putative XREs. The presence of all the XREs upstream of both genes suggested that some of the regulatory elements known to control CYP1A1 gene expression could also control CYP1A2 gene expression.

Jaiswal et al. (1987) inserted various lengths of DNA upstream from the human P1-450 gene into the promoterless pSVO-CAT prokaryotic expression vector and compared with mouse P1-450 upstream sequences similarly treated. The results were consistent with the presence of several functional regulatory regions within the upstream DNA: a promoter region, a region that is negatively autoregulated, and a region further upstream that activates transcription and is dependent upon a functional aromatic hydrocarbon receptor. Compared with 1,604 basepairs of human P1-450 upstream sequences, 1,646 basepairs of mouse P1-450 upstream sequences exhibited an increased sensitivity to TCDD; this effect was found to require both trans-acting protein factors and cis-acting DNA elements.

Thum and Borlak (2000) investigated the gene expression of major human cytochrome P450 genes in various regions of explanted hearts from 6 patients with dilated cardiomyopathy and 1 with transposition of the arterial trunk and 2 samples of normal heart. mRNA for cytochrome 1A1 was predominantly expressed in the right ventricle. A strong correlation between tissue-specific gene expression and enzyme activity was found. Thum and Borlak (2000) concluded that their findings showed that expression of genes for cytochrome P450 monooxgenases and verapamil metabolism are found predominantly in the right side of the heart, and suggested that this observation may explain the lack of efficacy of certain cardioselective drugs.

Schiering et al. (2017) showed that dysregulated expression of Cyp1a1 in mice depletes the reservoir of natural aryl hydrocarbon receptor (AHR; 600253) ligands, generating a quasi Ahr-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of Ahr-dependent type 3 innate lymphoid cells and T helper 17 cells, and increased susceptibility to enteric infection. The deleterious effects of excessive Ahr ligand degradation on intestinal immune functions could be counterbalanced by increasing the intake of Ahr ligands in the diet. Schiering et al. (2017) concluded that their data indicated that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasized the importance of feedback control in modulating AHR pathway activation.

Hildebrand et al. (1985) used a full-length cDNA for human 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible cytochrome P1-450 to study DNA from somatic hybrid cells. They assigned the gene to chromosome 15. Jaiswal and Nebert (1986) indicated that this locus is in the 15q22-qter segment, near MPI (154550). The P3-450 gene (CYP1A2) has also been located on chromosome 15; see 124060. See also CYP1B1 (601771).

Corchero et al. (2001) found that the CYP1A1 and CYP1A2 genes are separated by a 23-kb segment that contains no other open reading frames. They are in opposite orientation, revealing that they share a common 5-prime flanking region.

Hildebrand et al. (1985) showed that in the mouse, which has 2 dioxin-inducible P-450 genes, P1-450 and P3-450, the 2 genes are situated in the middle portion of chromosome 9 near the Mpi-1 locus, between Thy-1 and Pk-3. Treatment of mice with polycyclic aromatic hydrocarbons results in induction of P1-450 and P3-450. The mouse P1-450 and P3-450 genes have been cloned and shown to be coordinately regulated by the cytosolic receptor which is coded by the Ah locus and specifically binds the inducing chemicals.

By Southern blot analysis of DNA from hamster-mouse somatic cell hybrids, Tukey et al. (1984) demonstrated that the genes for P1-450 and P3-450 map to chromosome 9 in the mouse. The major regulatory gene controlling P1-450 induction in the mouse is located in the centromeric region of chromosome 12. Mouse chromosome 9 shows other homology of synteny with human 15.

Kouri et al. (1982) reported that individuals with the high-inducibility phenotype (present in approximately 10% of the human population) might be at greater risk than low-inducibility individuals for cigarette smoke-induced bronchogenic carcinoma. In a 3-generation family of 15 individuals, Petersen et al. (1991) showed that the high-CYP1A1-inducibility phenotype segregated concordantly with an infrequent polymorphic site located 450 bases downstream from the CYP1A1 gene. These findings were consistent with those of Kawajiri et al. (1986, 1990), who demonstrated an association between this polymorphism and an increased incidence of squamous cell lung cancer. Polycyclic aromatic hydrocarbons (PAHs) generated from the combustion of fossil fuels, and aromatic amines, which are present in cigarette smoke and other environmental media, present 2 classic environmental carcinogens.

Perera (1997) reviewed evidence on variation in susceptibility to the effects of carcinogens. CYP1A1 encodes a phase I cytochrome P450 enzyme that metabolizes PAHs such as benzo[a]pyrene (BP). About 10% of Caucasians have a highly inducible form of the enzyme that is associated with an increased risk of lung cancer in smokers. Although not all studies have been positive, in Japanese and certain Caucasian populations, increased lung cancer risk was correlated with 1 or both CYP1A1 polymorphisms: the so-called MSPI polymorphism and the closely-linked exon 7 (isoleucine-valine) polymorphism (Kawajiri et al., 1996; Nakachi et al., 1991; Xu et al., 1996). The greatest incremental lung cancer risk from the 'susceptible' CYP1A1 genotype was seen in light smokers (7 times the risk of light smokers without the genotype), whereas heavy smokers with this genotype had less than twice the risk of heavy smokers without the genotype. The proposed mechanism for the increased risk is higher CYP1A1 inducibility or enhanced catalytic activity of the valine-type CYP1A1 enzyme. Consistent with these mechanisms, Mooney et al. (1997) found that U. S. smoking volunteers with the exon 7 mutation had more PAH-DNA adducts in their white blood cells than did smokers without the variant. Perera (1997) stated that PAH-DNA adducts were also elevated in cord blood and placenta of newborns with the CYP1A1 MSP1 polymorphism, which suggested that the genetic polymorphism may increase risk from transplacental PAH exposure. In lung tissue of adults, adduct concentration correlated with CYP1A1 expression or enzyme activity. Perera (1997) noted that lung tumors of Japanese smokers were found to be significantly more likely to have p53 (191170) mutations if they had the susceptible CYP1A1 genotype. A failure to demonstrate genetic susceptibility through CYP1A1 polymorphism when exposure to the environmental carcinogen is heavy is observed with some other polymorphisms and carcinogenic exposures. It is possible that at higher exposures, the effects of the genetic traits are overwhelmed by the environmental insults.

Numerous studies have shown that maternal cigarette smoking during pregnancy is associated with reduced birth weight and increased risk of low birth weight, defined as weight less than 2,500 g. Maternal cigarette smoking has thus been identified as the single largest modifiable risk factor for intrauterine growth restriction in developed countries. However, not all women who smoke cigarettes during pregnancy have low-birth weight infants. Wang et al. (2002) studied whether the association between maternal cigarette smoking and infant birth weight differs by polymorphisms of 2 maternal metabolic genes: CYP1A1 and GSTT1 (600436). The CYP1A1 polymorphism was the Msp1 polymorphism (AA vs Aa and aa); the GSTT1 polymorphism was present versus absent. Wang et al. (2002) found that regardless of genotype, continuous maternal smoking during pregnancy was associated with a mean reduction of 377 g in birth weight. They found that for the CYP1A1 genotype, the estimated reduction in birth weight was 252 g for the AA genotype group, but was 520 g for the Aa/aa genotype group. For the GSTT1 genotype, they found the estimated reduction in birth weight was 285 g and 642 g for the present and absent genotype groups, respectively. When both CYP1A1 and GSTT1 genotypes were considered, Wang et al. (2002) found the greatest reduction in birth weight among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes. Among mothers who had not smoked during their pregnancy or during the 3 months prior to their pregnancy, genotype did not independently confer an adverse effect.

The CYP1A1 and CYP1A2 genes are oriented head-to-head on human chromosome 15; the 23.3-kb spacer region might contain distinct regulatory regions for one or the other of these genes, or the regulatory regions for the 2 genes may overlap one another. From 24 unrelated subjects of 5 major, geographically isolated subgroups, Jiang et al. (2005) resequenced both genes (all exons and all introns) plus some 3-prime flanking sequences and the entire spacer region (39.6 kb total). They identified 85 SNPs, 49 of which were not in the NCBI database. SNP typing in 94 Africans, 96 Asians, and 83 Caucasians demonstrated striking ethnic differences in SNP frequencies and haplotype evolution. To demonstrate functionality, they generated a 'humanized' BAC transgenic mouse line, having an absence of the mouse orthologous Cyp1a1 or Cyp1a2 genes, that expressed human CYP1A1 and CYP1A2 mRNA, protein, and enzyme activity in a tissue-specific manner similar to that of the mouse.

Jones et al. (1991) coupled a DNA fragment containing the murine Cyp1a-1 enhancer elements and promoter region to the chloramphenicol acetyltransferase (CAT) reporter gene and used it to create transgenic mice. Treatment with 3-methylcholanthrene increased hepatic expression levels by as much as 10,000-fold. Differences in the response to induction between male and female mice suggested that Cyp1a-1 expression may be governed in a gender-related manner.

Paolini et al. (1999) found significant increases in the carcinogen-metabolizing enzymes CYP1A1, CYP1A2, CYP3A (124010), CYP2B (123930), and CYP2A in the lungs of rats supplemented with high doses of beta-carotene. The authors suggested that correspondingly high levels of CYPs in humans would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens, thus explaining the cocarcinogenic effect of beta-carotene in smokers.

The nomenclature and symbolization of the P450 enzymes and their genes have gone through many changes. The currently preferred system (Nebert, 1988) uses the symbol CYP followed by a number for family and a letter for subfamily. CYP1 is the designation of the family of P450 genes located on human chromosome 15 and mouse chromosome 9. (CYP1 was previously used for a P450 gene on chromosome 19 (122720), which is now called CYP2.) The number assigned to the family is sometimes arbitrary or selected for reasons of historical priority; in other cases it has specific significance, e.g., in the case of CYP21 on 6p and CYP17 on 10, which are genes for the enzymes of classes designated P450XXI (steroid 21-hydroxylase) and P450XVII (steroid 17-alpha-hydroxylase), respectively.

From study of mouse-human hybrid cells, Brown et al. (1976) concluded that a structural gene for AHH is on chromosome 2 and that possibly a regulatory gene is there also. Ocraft et al. (1985) localized the gene to 2q31-2pter. According to McBride (1985), the gene mapped to chromosome 2 by expression assays is almost certainly not the structural locus; the structural locus is that assigned to chromosome 15: dioxin-inducible P1-450. Nebert (1988) recommended that the AHH locus held to be on chromosome 2 be removed from that listing. The assignment was based on measurements of AHH inducibility in tissue culture, and effects of dibutyryl cAMP or other factor on the enzyme activity might have been observed. Neither the Ah receptor nor the P(1)450 or P(3)450 genes that it regulates map to chromosome 2 or to its mouse or hamster homolog.

The chloramphenicol acetyltransferase (CAT) assay system for monitoring gene expression was reported by Gorman et al. (1983). Gorman (1993) described the circumstances surrounding the development of the method. The initial report was turned down by the journal Nature, whose editorial staff charged that the work was not of wide enough interest for publication there.