Disease relevance of CYP1A2

• Because CYP1A2 activity has been shown to vary up to 60-fold among patients, we proposed that a convenient measure of CYP1A2 activity, the [(13)C 3-methyl] caffeine breath test (CBT), might be clinically useful in identifying patients most susceptible to tacrine liver toxicity [1].
• Three forms, designated CYP1A2, CYP3A3, and CYP3A4, were able to catalyze significant production of DNA-bound metabolites of 20-, 8-, and 5-fold, respectively, above binding catalyzed by Hep G2 cells infected with wild-type vaccinia virus [2].
• These data indicate that maternal mouse hepatic CYP1A2, by sequestering dioxin and thus altering the pharmacokinetics, protects the embryos from toxicity and birth defects; substitution of the human CYP1A2 trans-gene provides the same protection [3].
• Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis [4].
• In order to investigate further the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, and since the specificity of anti-LM autoantibodies towards CYP1A2 has been determined, the antigenic site was further localized [4].

Psychiatry related information on CYP1A2

• Our objective was to determine the time course of CYP1A2 activity changes after smoking cessation in heavy smokers as the basis for dosing adaptation schemes [5].
• Plasma lutein explained the largest portion of the variance (7%) and was negatively associated with CYP1A2 activity (p < 0.01), as were use of menopausal replacement estrogens (p = 0.04), plasma alpha-tocopherol (p = 0.05) and alcohol consumption (p = < 0.01) [6].
• After adjustment for these variables, no association was found between CYP1A2 activity and sex, race, age, education, smoking, physical activity, weight, vitamin E supplements, the other plasma micronutrients measured, and dietary intakes of red meat, processed meat and cruciferous vegetables [6].
• Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease [7].
• In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated [8].

High impact information on CYP1A2

• The purpose of this investigation was to determine the specificity of cytochromes P1-450 and P3-450 toward the metabolic activation of these arylamines [9].
• Cytochrome P3-450, a single isoform of the cytochrome P-450 supergene family, bioactivated these food mutagens [9].
• On days 5 and 12, hepatic CYP3A4 and CYP1A2 activities were measured and colon biopsies were performed [10].
• 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) [10].
• CONCLUSIONS: LKM antibodies in APS-1 sera are specifically directed against CYP1A2 or CYP2A6, but their diagnostic and prognostic significance for liver disease remain to be determined [11].

Chemical compound and disease context of CYP1A2

• Acetaminophen (INN, paracetamol), a widely used and effective analgesic and antipyretic agent, causes serious hepatic and renal toxicity at high doses by conversion of acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) through CYP1A2, CYP2E1, and CYP3A4 [12].
• Recombinant CYP3A4 expressed in Escherichia coli showed N-dealkylation activity of fentanyl and sufentanil, while expressed CYP1A2, 2C10, and 2E1 enzymes did not [13].
• 1. We have examined the metabolism of diazepam by ten human cytochrome P450 forms (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5) expressed in HepG2 cells using a recombinant vaccinia virus system [14].
• In addition, the procarcinogens 2AAF and PhIP were efficiently bioactivated to bacterial mutagens when incubated with Escherichia coli membranes expressing CYP1A2 and NADPH reductase [15].
• We conclude that inhibition of CYP1A2 by fluvoxamine considerably reduces elimination of lidocaine and may increase the risk of lidocaine toxicity [16].

Biological context of CYP1A2

• Using the humanized hCYP1A1_1A2 transgenic mouse (expressing the human CYP1A1 and CYP1A2 genes in the absence of mouse Cyp1a2 gene), the teratogenic effects of dioxin reverted to the wild-type phenotype [3].
• Between the human CYP1A2 and CYP1A1 (cytochrome P(1)450) genes, exons 2, 4, 6, and especially 5 are strikingly conserved in both nucleotide similarity and total number of bases [17].
• This result may reflect significant genetic differences in constitutive and/or inducible CYP1A2 gene expression that could play an important role in individual risk of environmental toxicity or cancer [17].
• The canonical 5-bp box (CACGC), found upstream of all mammalian CYP1A1 genes to date and believed to interact with the inducer.aromatic hydrocarbon receptor complex, was not found on either strand in the 1,906 bp of the 5' flanking region of human CYP1A2 [17].
• RESULTS: There were no sex differences associated with CYP1A2 activity [18].

Anatomical context of CYP1A2

• Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules [19].
• Human liver microsome incubations performed with specific inhibitors of these three CYP isozymes have shown up to 60% inhibition of demethylcitalopram production. cDNA expressed human cytochrome P-450 3A4, 2C19 and 2D6 isozymes, but not CYP1A2, were identified to be involved in N-demethylation of CIT enantiomers [20].
• Furthermore, pradefovir at 10 microg/ml was not an inducer of either CYP1A2 or CYP3A4/5 in primary cultures of human hepatocytes [21].
• We found that CYP1A2 can be induced significantly by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (MC), or benz[a]anthracene in the human colon carcinoma cell line LS180 [22].
• Therefore, at therapeutically relevant concentrations of O6-benzylguanine, CYP1A2 could be primarily involved in its oxidation since it shows a much lower Km value (1.3 microM) than CYP3A4 (52.2 microM) and cytosol (81.5 microM) [23].

Associations of CYP1A2 with chemical compounds

• However, the correlation we observed between CBT results and tacrine blood levels is the first evidence supporting a critical role for CYP1A2 activity in the disposition of the drug in vivo [1].
• RESULTS: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84) [24].
• The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity [25].
• This suggests that induction of CYP1A2 activity by omeprazole is unlikely to increase the risk of acetaminophen hepatotoxicity [12].
• The results of this study show that, despite induction of CYP1A2 activity in slow metabolizers (a 75% increase in plasma clearance of caffeine), the formation of NAPQI from acetaminophen was not increased after 7 days of omeprazole administration (40 mg/day) [12].

Physical interactions of CYP1A2

• In a previous study, when 4-ethylDDC and NADPH interacted with human liver microsomes possessing elevated levels of CYP1A2 and 2C9, N-ethylprotoporphyrin IX (N-ethylPP) was not formed despite the fact that it was formed in microsomes from baculovirus-infected insect cell lines (BIICL) containing either CYP1A2 or 2C9 [26].
• 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 [27].
• Taken together with the lack of a kinetically detectable interaction between CYP2B4 and CYP2E1, and the previously reported CYP1A2-CYP2B4 interaction, these results suggest that CYP1A2 may facilitate the formation of complexes with other P450 enzymes [28].
• The chloroplast protein CP12 is known to play a leading role in a complex formation with the enzymes GAPDH and PRK [29].

Enzymatic interactions of CYP1A2

• Mexiletine is mainly catalyzed by CYP2D6 and partially catalyzed by CYP1A2 [30].
• Sixteen healthy non-smoking subjects, two females and 14 males, were exposed to three different types of diets and afterwards assayed for CYP1A2 catalysed caffeine metabolites and for CYP2E1 catalysed 6-hydroxylation of chlorzoxazone [31].
• In humans, CYP1A2 catalyzed N-hydroxylation and subsequent UGT1A-mediated glucuronidation is a dominant pathway in the metabolism of PhIP [32].
• In sonicate from transiently transfected COS cells, NAT1 increased CYP1A2 catalyzed adduct formation 4-fold while NAT2 increased adduct formation 12-fold [33].

Regulatory relationships of CYP1A2

• The LS180 cell line should constitute a good model for further mechanistic studies on AHR-regulated CYP1A2 expression [22].
• However, the Km values of the expressed CYP1A2 (approximately 15 microM) were almost identical with those of the expressed CYP2D6 (approximately 22 microM) and human liver microsomes [34].
• 5. In conclusion, xenobiotics inducing CYP1A1 mRNA expression have been shown also to induce CYP1A2 and CYP1B1, differing only with regard to level and time course of induction [35].
• 5. The metabolism of 20 microM BFC in human liver microsomes was inhibited to 37-48% of control by 5-100 microM of the mechanism-based CYP1A2 inhibitor furafylline and to 64-69% of control by 5-100 microM of the mechanism-based CYP3A4 inhibitor troleandomycin [36].
• In contrast, in HeLa (human cervical adenocarcinoma) cells, CYP1A1 and CYP1B1 were induced by TCDD by up to 2-3-fold but CYP1A2 was not detected even when the cells were treated with TCDD [37].

Other interactions of CYP1A2

• No significant changes in either CYP1A2 or CYP2D6 activities were observed between placebo and treatment arms of the study [38].
• Although the induction of CYP1A2 may be of some clinical relevance, the small inhibition of CYP2C19 is probably unimportant [39].
• These results show that AHR-independent pathway(s) can be involved in induction of CYP1A2 and CYP1B1 [40].
• Formation of 3-hydroxymethylantipyrine is mediated by CYP1A2 and CYP2C9 [41].
• Methoxychlor and S-mephenytoin inhibited expressed CYP2B6 but not CYP1A2 mediated 7-EFC O-deethylation [42].

Analytical, diagnostic and therapeutic context of CYP1A2

• The low-activity COMT and CYP1A2 variant alleles were weakly related to lower percent mammographic density after adjustment for age, ethnicity, body mass index and reproductive variables (p for gene-dosage =0.08 and 0.05, respectively) [43].
• Investigations of protein and mRNA expression of basal and induced CYP1A2 and CYP3A4 after ALR treatment by Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively, suggest a regulation on the transcriptional level [44].
• Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene [22].
• TCDD and MC each caused a dramatic elevation of CYP1A2 mRNA, as assessed by reverse transcription-polymerase chain reaction or by northern blot analysis [22].
• It has been difficult to study the regulation of cytochrome P4501A2 (CYP1A2) because expression of this enzyme is reported to be limited or absent in cell culture [22].

References