Disease relevance of Cyp1a2

• Fetuses from Cyp1a2(-/-) dams exhibited a approximately 6-fold increased sensitivity to cleft palate, hydronephrosis, and lethality [1].
• In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1 [2].
• Endpoints such as thymic involution, Cyp1a2 induction, hepatomegaly, and hydropic degeneration remain unchanged in this model [3].
• The incidence of lymphoma was higher in Cyp1a2-null females than wild-type females treated with low dose (600 nmol) PhIP whereas no significant differences were observed in other treatment groups of mice [4].
• Higher incidences of hepatocellular adenoma were observed in Cyp1a2-null female and male mice as compared with wild-type mice [4].

High impact information on Cyp1a2

• In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(-/-) mouse [5].
• Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene [6].
• CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines [6].
• To define better the developmental and metabolic functions of this enzyme, we developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells [6].
• Expression of CYP1A2 is induced after exposure to certain aromatic hydrocarbons (i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin) [7].

Chemical compound and disease context of Cyp1a2

• Role of CYP2A5 and 2G1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the Cyp1a2(-/-) mouse [8].
• Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice [9].
• To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2) [10].
• Male (BALB/c x DBA/2) F(1) mice were given 3-amino-1,4-dimethyl-5H-pyrido [4,3-b] indole acetate (Trp-P-1; 20 mg/kg body weight) by gavage at 24-h intervals for 1 or 2 weeks, and the effects of Trp-P-1 on the levels of serum total testosterone and hepatic cytochrome P4501a2 (Cyp1a2) were examined [11].
• Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice [12].

Biological context of Cyp1a2

• To fetuses carried by Cyp1a2(-/-) dams, however, this dose of dioxin was lethal; this effect was absolutely dependent on the maternal Cyp1a2 genotype and independent of the embryonic Cyp1a2 genotype [1].
• 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 [1].
• Thus, tricyclic hydrocarbons induce Cyp1a2 without the co-induction of Cyp1a1 and therefore these relatively non-toxic compounds can be used to further probe the role of Cyp1a2 in the metabolism and metabolic activation of diverse chemical carcinogens [13].
• The basal levels of the luciferase reporter in liver were expressed much higher than other tissues, which correlated well with the endogenous Cyp1a2 mRNA tissue distribution [14].
• The differential inducibility of liver CYP1A1 mRNA by dioxin was therefore compared in Cyp1a2(+/+) wild-type mice, Cyp1a2(+/-) heterozygotes, and Cyp1a2(-/-) homozygous null mutants [15].

Anatomical context of Cyp1a2

• Dioxin levels were highest in adipose tissue, mammary gland, and circulating blood of Cyp1a2(-/-) mothers, compared with that in the Cyp1(+/+) mothers, who showed highest dioxin levels in liver [1].
• Cell-density-dependent expression of Cyp1a2 gene in monolayer-cultured adult mouse hepatocytes [16].
• Cyp1a2 protects against reactive oxygen production in mouse liver microsomes [17].
• In Cyp1a2(-/-) mice, H(2)O(2) production was the same for induced and noninduced microsomes, with levels significantly higher than those in wild-type mice [17].
• Histological examination confirmed a decrease in hepatocellular damage in TCDD-treated Cyp1a2(-/-) mice; in particular, there was no bile duct damage or proliferation that in the Cyp1a2(+/+) mice might be caused by uroporphyrin [18].

Associations of Cyp1a2 with chemical compounds

• More dioxin reached the embryos from Cyp1a2(-/-) dams, compared with that from Cyp1(+/+) dams [1].
• Acenaphthylene was the most potent inducer of MROD, a Cyp1a2-dependent activity, and was utilized as a prototypical inducer for this group of tricyclic hydrocarbons [13].
• However, phenobarbital induction was unexpectedly higher, while beta-naphthoflavone induction of the reporter was much lower than that of the endogenous Cyp1a2 gene [14].
• Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (-/-) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13) [19].
• The induction of P450 cytochromes Cyp1a1 and Cyp1a2 in the liver of male mice differing in sensitivity to the carcinogenic effect of o-aminoazotoluene (OAT) has been studied [20].

Regulatory relationships of Cyp1a2

• The level of Cyp1a2 mRNA was suppressed to 67% by IL-6 and 59% by TNF-alpha [21].
• In this study, CYP1A2 was induced in hepatocytes exposed to the histone deacetylase inhibitors trichostatin A (TSA) and sodium butyrate (SB), but only well after constitutive CYP1A2 expression was silenced [22].

Other interactions of Cyp1a2

• In the DB[a,l]P-treated mice, levels of DNA adducts were significantly lower in Cyp1a2(-/-) and Cyp1b1(-/-) mice by 57 and 46%, respectively, as compared to wild-type (WT) mice (C57BL/6 background) [23].
• Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1 [2].
• To test the combined roles of CYP1A2 and CYP2E1 in an intact animal model, a double-null mouse line lacking functional expression of CYP1A2 and CYP2E1 was produced by cross-breeding Cyp1a2-/- mice with Cyp2e1-/- mice [24].
• Lower basal Cyp1a2 mRNA levels and lower expression of Cyp1a2 and Cyp3a11 mRNAs after APAP dosing were also observed in females compared with males [25].
• Regulation of CYP1A2 by histone deacetylase inhibitors in mouse hepatocytes [22].

Analytical, diagnostic and therapeutic context of Cyp1a2

• In situ hybridization of Cyp1a1, Cyp1a2 and Ah receptor mRNAs expressed in murine ocular tissues [26].
• The level of Cyp1a1 and Cyp1a2 mRNA was assayed by quantitative competitive polymerase chain reaction (PCR) [20].
• Treatment with MC increased hepatic CYP1A1 in both mouse lines and hepatic CYP1A2 only in the Cyp1a2(+/+) line, as determined by Western immunoblotting [27].
• Significant upregulation of Cyp1a2 was noted at beta-NF doses as low as 0.62 and 1.2 mg/kg when gene expression was measured by microarray or Northern blotting, respectively [28].
• We have used cDNA microarray analysis of the untreated Cyp1a2(-/-) knockout mouse to search for changes in gene expression that might indicate important intrinsic roles for this enzyme [29].

References