Disease relevance of Cyp2a5

• In hepatomas from female mice, only the Cyp2a-5 form was overexpressed (2-3 fold) [1].
• Targeted disruption of the olfactory mucosa-specific Cyp2g1 gene: impact on acetaminophen toxicity in the lateral nasal gland, and tissue-selective effects on Cyp2a5 expression [2].

High impact information on Cyp2a5

• Proteins encoded by both the Cyp2a4 and Cyp2a5 genes also display daily variation in accumulation, though this is more dramatic for CYP2A4 than for CYP2A5 [3].
• Mouse coumarin 7-hydroxylase P-450 2a-5 contains Val at position 117, but it exhibits very low DHEA hydroxylase activity [4].
• Our data support the proposition that the region of the Coh locus on chromosome 7 is the site of the cytochrome P-450PB gene family [5].
• The Coh locus has previously been shown to code for a phenobarbital-inducible enzyme, believed to be a cytochrome P-450, which catalyzes the conversion of coumarin to 7-hydroxycoumarin (umbelliferone) [6].
• Using the BXD recombinant inbred strains, five of these polymorphisms were mapped to the Coh (coumarin hydroxylase) locus on chromosome 7 of the mouse [6].

Chemical compound and disease context of Cyp2a5

• Pyrazole, a strong inducer of Cyp2a-5 in normal mouse livers, also increases this isozyme in hepatomas [7].
• Increased expression of Cyp2a-5 was associated with an increase in coumarin 7-hydroxylation, a marker activity of Cyp2a-5, and the corresponding mRNA, suggesting that regulation of Cyp2a-5 in hepatomas is pretranslational [7].

Biological context of Cyp2a5

• Close linkage of the cytochrome P450IIA gene subfamily (Cyp2a) to Cyp2b and Coh on mouse chromosome 7 [8].
• The theoretical pI values, determined from the amino acid sequence, were pI 9.91 for Cyp2a-4 and pI 10.01 for Cyp2a-5 [1].
• Transfection experiments combined with mutation of the XRE site indicated that the site partly mediates the TCDD induction of Cyp2a5 [9].
• Secondly, the coordinated up-regulation of the HO-1 and Cyp2a5 during Cd-mediated injury implicates a network of enzyme systems in the maintenance of balancing BR production and elimination [10].
• The induction of Cyp2a5, QOR, and GSTYa catalytic activity and gene expression occurred primarily in kidney during or shortly after conditions of oxidant stress [11].

Anatomical context of Cyp2a5

• Coumarin 7-hydroxylase activity was 20 pmol/mg/min. in mouse and 4 pmol/mg/min. in rat lung microsomes [12].
• These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines [13].
• Expression of type I and II in COS-1 cells revealed that the latter catalyzed coumarin 7-hydroxylase activity at 10 to approximately 14 pmol min-1 (mg of cellular protein)-1 [14].
• Metyrapone clearly inhibited COH in mouse liver microsomes, but interestingly it had no effect on COH activity in human liver microsomes, although these two isozymes have earlier been shown to be immunologically similar [15].
• From 100 G418-resistant clones initially isolated, three cell lines were chosen for further study based upon their morphologies, growth rates and CYP2A6-dependent coumarin 7-hydroxylase activities [16].

Associations of Cyp2a5 with chemical compounds

• Together with previous reports [Aida & Negishi (1991) Biochemistry 30, 8041-8045], the current data suggest that both pyrazole and cobalt increase COH catalytic activity by affecting Cyp2a-5 by post-transcriptional mechanisms in mice [17].
• Pyrazole, cobalt and phenobarbital increase the activity of coumarin 7-hydroxylase (COH) in mouse liver [17].
• Three and 4 days after the cerium treatment, coinciding with the occurrence of overt liver damage, there was a dramatic decrease in COH activity [18].
• Two days after the administration of a hepatotoxic dose of cerium chloride (2 mg/kg i.v.), COH activity was increased 3.2-fold in the liver of DBA/2 mice [18].
• Anti-Cyp2a-5 antibody effectively inhibited mouse and rat lung coumarin 7-hydroxylase and testosterone 15 alpha-hydroxylations but failed to block these activities in the rat liver [12].

Enzymatic interactions of Cyp2a5

• Cytochrome P450 2A5-catalyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50% [19].

Co-localisations of Cyp2a5

• A P450 protein co-migrating with Cyp2a-5 was also detected in rat lung microsomes [12].
• The CYP2A5 mRNA and the corresponding protein co-localized at most sites and were predominantly detected in the olfactory region, with an expression in sustentacular cells, Bowman's gland, and duct cells [20].

Regulatory relationships of Cyp2a5

• These data indicate that the Cyp2a-4/5 complex is regulated in a different way in DBA/2 and C57BL/6 mice and that some association exists between the development of liver damage and COH induction [18].
• An additional AHR-dependent mechanism also regulates the proximal promoter of the Cyp2a5 gene [9].
• The cytochrome P4502a5 (Cyp2a5) gene is expressed principally in liver and olfactory mucosa [21].

Other interactions of Cyp2a5

• Pulmonary coumarin 7-hydroxylase, testosterone hydroxylase and other P450-mediated activities were compared in the mouse and rat [12].
• Anti-Cyp2a-5 antibody recognized a 50-kDa protein in 50% of the fetal adrenals [22].
• Regulation of the Cyp2a5 gene involves an aryl hydrocarbon receptor-dependent pathway [9].
• Unexpectedly, a significant reduction in the expression of the Cyp2a5 gene was found in the liver, the lateral nasal gland (LNG), and, to a lesser extent, the kidney of adult Cyp2g1-null mice [2].
• Collectively, these results indicate that the hnRNP A1 is an important regulator of the Cyp2a5 gene [23].

Analytical, diagnostic and therapeutic context of Cyp2a5

• PCR amplification of a 1 kb region in Cyp2a-4/5-mRNA-derived cDNA, followed by cutting at the diagnostic PstI site, showed that most of the steady-state mRNA consisted of Cyp2a-5, which is also the form most affected by pyrazole [17].
• This protein was identified as Cyp2a-5, by the use of immunoblots obtained from isoelectric focusing gels [1].
• Extrahepatic increases in CYP were observed only in non-AHR dependent isozymes in the kidney, where both Cyp2a5 mRNA and catalytic activity increased maximally 24 h after treatment [11].
• This apparent increase in the expression of Cyp2a-5 was verified by Northern blot and Western blot analyses and by determining the enzymatic activity, coumarin 7-hydroxylase, in hepatic tissue [24].
• Breast microsomal coumarin-7-hydroxylase activity paralleled the developmental pattern observed for CYP2A3 on Western blots [25].

References