Disease relevance of CYP1A1

• No evidence was found of associations between GSTT1 deficiency or the CYP1A1 valine variant and lung cancer risk due to ETS exposure [1].
• We conducted a population-based case-control study in six San Francisco Bay area counties from 1994 to 2001 to investigate associations between polymorphisms in genes for two carcinogen-metabolizing enzymes (cytochrome P450 1A1 [CYP1A1] and glutathione S-transferase [GST]), smoking, and adenocarcinoma of the exocrine pancreas [2].
• In human hepatoma HepG2 cells, which lack functional ER, alpha-endosulfan, but not 17beta-estradiol, displays a repressive effect on CYP1A1 through a different mechanism [3].
• Cases with Ile/Val at CYP1A1 codon 462 were 2.6-fold and those with Val/Val were 5.1-fold more likely to have first-degree relatives with breast cancer than those with Ile/Ile (P = 0.002) [4].
• These data are consistent with the idea that CYP1A1 and CYP1B1 activation leads to 5F-203 toxicity through DNA damage-induced apoptosis, as well as signaling through a variant member of the TGF-beta superfamily [5].

Psychiatry related information on CYP1A1

• Individual difference in expression levels of Ahr and Arnt mRNAs was observed, and the expression levels of CYP1A1 appeared to associate with those of transcriptional factors [6].
• Aromatic DNA adducts in foundry workers in relation to exposure, life style and CYP1A1 and glutathione transferase M1 genotype [7].
• Gene-environment interaction analysis showed that CYP1A1 Val/Val genotype, GSTM1 deletion genotype had synergetic interactions with tobacco smoking, alcohol drinking and family history of EC [8].
• Effects of dietary habits and CYP1A1 polymorphisms on blood dioxin concentrations in Japanese men [9].
• CYP1A1 rs2606345 was related to estrogen metabolite concentrations, vasomotor symptoms, and depressive symptoms [10].

High impact information on CYP1A1

• This cell line was used to isolate a human P1-450 full-length complementary DNA (cDNA) clone [11].
• Human dioxin-inducible cytochrome P1-450: complementary DNA and amino acid sequence [11].
• Enzyme induction reflects increased transcription of the cognate CYP1A1 gene [12].
• MAIN OUTCOME MEASURE: Birth weight, gestation, fetal growth by smoking status and CYP1A1 MspI (AA vs Aa and aa, where Aa and aa were combined because of small numbers of aa and similar results), and GSTT1 (present vs absent) genotypes [13].
• When CYP1A1 genotype was considered, the estimated reduction in birth weight was 252 g (SE, 111 g) for the AA genotype group (n = 75; OR, 1.3; 95% CI, 0.6-2.6), but was 520 g (SE, 124 g) for the Aa/aa genotype group (n = 43 for Aa, n = 6 for aa; OR, 3.2; 95% CI, 1.6-6.4) [13].

Chemical compound and disease context of CYP1A1

• We previously described an inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced CYP1A1 mRNA and enzyme activity by transforming growth factor-beta1 (TGF-beta1) in human lung cancer A549 cells [14].
• Resveratrol was also effective in inhibiting CYP1A1 transcription induced by the aryl hydrocarbon dimethylbenz[a]anthracene in human mammary carcinoma MCF-7 cells [15].
• RESULTS: CYP1A1 codon 462 Ile/Val or Val/Val variants and the CYP1B1 codon 432 Leu/Val variant were found more in breast cancer patients </=35 years of age at onset than the common homozygote [odds ratio (OR), 1.6 and 1.7, respectively] [4].
• In the present study we have examined the effect of the common dietary polyphenolic compounds quercetin and kaempferol on the transcription of CYP1A1 and the function of the AhR in MCF-7 human breast cancer cells [16].
• On the other hand, a recently described mutation in exon 7 of CYP1A1 gene (threonine exchanged to asparagine in codon 461) showed a strong association with endometrial cancer risk with an odds ratio of 6.36 (95% confidence interval: 1.99-26.5, P = 0.0004) [17].

Biological context of CYP1A1

• The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1 substrates, including polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a metabolic by-product [18].
• RNA interference studies with T47D cells support a role for ERalpha in TCDD-dependent CYP1A1 expression [19].
• The CYP1A1 (m) "variant" genotype, which contains at least one copy of the CYP1A1 variant alleles, was found to be associated with a 2.1-fold [95% confidence interval (CI), 1.1-3.9] increase in the risk of RCC [20].
• These data underline the major importance of the CYP1A1 inducibility phenotype associated with the homozygous GSTM1 null genotype in chemically induced cancers [21].
• Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage [22].

Anatomical context of CYP1A1

• There was an inverse correlation between the level of peripheral polycyclic aromatic hydrocarbon DNA adducts measured on day 11 and both liver CYP1A2 activity (P = 0.027) and enterocyte CYP1A1 protein concentration (P = 0.046) [23].
• These results show that xenoestrogens, by altering the ratio of CYP1B1/CYP1A1, could redirect estradiol metabolism in a more toxic pathway in the breast cell line MCF-7 [3].
• Association of CYP1A1 germ line polymorphisms with mutations of the p53 gene in lung cancer [24].
• Because CYP1A1 is one of the primary carcinogen-activating enzymes in oral mucosa, the use of curcumin as an oral cavity chemopreventive agent could have significant clinical impact via its ability to inhibit carcinogen bioactivation [25].
• Results of our metabolism studies showed that curcumin significantly inhibited CYP1A1-mediated benzo(a)pyrene diol bioactivation in both oral SCC cells and intact oral mucosa [25].

Associations of CYP1A1 with chemical compounds

• Using chromatin immunoprecipitation assays, we studied the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated recruitment of the aryl hydrocarbon receptor (AhR) and several co-regulators to the CYP1A1 promoter [19].
• Interestingly, estrogen receptor alpha (ERalpha) displayed a TCDD- and time-dependent recruitment to the CYP1A1 promoter, which was increased by co-treatment with estradiol [19].
• Treatment of LS-174 cells with nontoxic doses of DIM, ASG, I3C, or ICZ affected an increase of up to 21-fold in cytochrome P450 1A1 (CYP1A1) [26].
• Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics [22].
• Treatment of the cells with diosmin or diosmetin, on the other hand, caused a dose- and time-dependent increase in CYP1A1 activity in intact cells that was comparable to that induced by DMBA or by the aryl hydrocarbon benzo(a)pyrene [27].

Physical interactions of CYP1A1

• Indeed, some xenobiotics do activate CYP1A1 gene expression in spite of their inability to compete with TCDD for binding to the AhR [28].
• Thus formed AhR/Arnt heterodimer binds a specific DNA sequence designated XRE in the promoter region of the target genes including CYP1A1, UDP-glucuronosyl transferase and others to enhance their expression [29].
• The in silico docking of AAI to the active sites of CYP1A1 and 1A2 indicates that AAI binds as an axial ligand of the heme iron and that the nitro group of AAI is in close vicinity to the heme iron of CYP1A2 in an orientation allowing the efficient reduction of this group observed experimentally [30].
• Modulation of CYP1A1-mediated oxidation of carcinogenic azo dye Sudan I and its binding to DNA by cytochrome b5 [31].
• Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha heterodimer [32].

Enzymatic interactions of CYP1A1

• CYP1B1 catalyzed benzo[a]pyrene 3-hydroxylation at rates lower than those of CYP1A1 but higher than those of CYP1A2 [33].
• In vitro and whole-cell metabolic activity studies showed that the periplasmically-located CYP1A1 competently catalysed NADPH-dependent benzo[a]pyrene 3-hydroxylation and 7-ethoxyresorufin O-deethylation [34].

Regulatory relationships of CYP1A1

• Polyinosinic acid-polycytidylic acid down regulated the constitutive and pyridine-induced expression of CYP2E1 and the pyridine- and beta-naphthoflavone-induced expression of CYP1A1 as demonstrated by metabolic activity and immunoblot analyses [35].
• CYP1B1 mRNA was consistently expressed in both normal and neoplastic kidney while CYP1A1 was present in the majority of normal and neoplastic whereas CYP1A2 was infrequently expressed [36].
• Like other groups we found that 10 nM TCDD inhibits cell growth and induces cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) activity in MCF-7 cells expressing the estradiol receptor (ER) [37].
• In transiently transfected MCF-7 human breast cancer cells, overexpression of COUP-TFI inhibited TCDD-activated reporter gene activity from the CYP1A1 promoter [38].
• In addition, the hAhR/L678A failed to activate CYP1A1 gene transcription in transfected BP-8 cells and exhibited reduced binding to RIP140 in vitro [39].

Other interactions of CYP1A1

• Evidence for a new human CYP1A1 regulation pathway involving PPAR-alpha and 2 PPRE sites [32].
• Treatment of the colon cell line with ICZ or SUL caused increases in the levels of mRNA for CYP1A1, AKR1C1, and NQO1 that were consistent with the enzyme data [26].
• There was also a higher risk of RCC for subjects with the CYP1A1 (m) variant genotype combined with any of the following genotypes: GSTT1 (+) "active" [odds ratio (OR), 2.3; 95% CI, 1.2-4.5], GSTP1 (m) variant (OR, 2.4; 95% CI, 1.0-5.4), or NAT2 (-) "slow acetylator" (OR, 2.5; 95% CI, 1.1-5.5) [20].
• CYP2C19 may have a role in bladder cancer risk, but polymorphisms in CYP1A1 and 2E1 had no statistically significant impact [40].
• Thus, we conclude that (a) CYP3A4 and CYP1A1 are the predominant cytochrome P450 enzymes that catalyze BPU metabolism, (b) BPU is metabolized to two cytotoxic and four noncytotoxic metabolites, and (c) ritonavir inhibits BPU metabolism to improve the systemic exposure to BPU without altering cumulative exposure to BPU and the cytotoxic metabolites [41].

Analytical, diagnostic and therapeutic context of CYP1A1

• Induction of hepatic CYP1A1 by PBO or ACN was not detected by northern blots [42].
• EXPERIMENTAL DESIGN: AhR, CYP1B1, and CYP1A1 expression was examined in 107 lung adenocarcinomas and 57 BAC by immunohistochemistry [43].
• Western blot analysis showed that cynomolgus monkey hepatic microsomes constitutively express P450s immunologically related to the human CYP3A, CYP2C, and low levels of CYP1A1 [44].
• A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting [45].
• In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype [46].

References