High impact information on CYP1A4

• The P-450s exhibit catalytic selectivity either for arachidonic acid metabolism, particularly epoxygenation (P-450 TCDDAA, 55 kDa), or for aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin deethylase (7-EROD) (P-450 TCDDAHH, 54.5 kDa) [1].
• Inducibility of the cytochrome P4501A4 (CYP1A4) enzyme, measured as ethoxyresorufin-O-deethylase (EROD) activity, has been used as a biomarker for sensitivity to the effects of dioxin-like compounds in avian species [2].
• Spatial heterogeneity in phylogenetic signal along the sequences strongly indicated that cormorant CYP1A4 and CYP1A5 have undergone partial interparalog gene conversion, similar to chicken and mammalian CYP1As [3].
• Hepatic CYP1A4 and CYP1A5 mRNA levels in wild cormorants from Lake Biwa, Japan, were quantified to examine the effects of DRCs on isoform-specific expression and to evaluate the toxicokinetics of DRCs in which CYP1A expression is involved [3].
• Effect of arsenite on the induction of CYP1A4 and CYP1A5 in cultured chick embryo hepatocytes [4].

Biological context of CYP1A4

• Phylogenetic analysis of complete coding sequences suggests that mammalian and bird paralog pairs (CYP1A1/2 and CYP1A4/5, respectively) are the result of independent gene duplication events [5].
• Together, these data indicate that avian and mammalian CYP1A paralog pairs resulted from a single gene duplication event and that extensive gene conversion is responsible for the exceptionally high degree of sequence similarity between CYP1A4 and CYP1A5 [5].
• AhR was expressed continuously in the heart and liver during embryogenesis, whereas induction of CYP1A4 and CYP1A5 by TCDD was detected only in the liver [6].

Anatomical context of CYP1A4

• Thus, CYP1A5 appears to be regulated in a very similar manner to CYP1A4 in chick embryo liver [7].
• Concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on CYP1A4 and CYP1A5 mRNA abundance were detected in fresh and post-EROD hepatocyte cultures [2].
• CYP1A4 alone was extensively induced in the cardiovascular system, in cardiac myocytes, in perivascular cells having the same location as impulse-conducting Purkinje cells, and like CYP1A1, in vascular endothelium in every organ examined [8].
• Western blots of liver microsomes using polyclonal antisera to chick embryo-derived CYP1A4 and 1A5 recognized two TCDD-induced bands in each of the species [9].
• Also, TCDD induced CYP1A4 but not 1A5 in both myocardium and heart vessels whereas CYP1A1 induction has only been found in endocardium [10].

Associations of CYP1A4 with chemical compounds

• TCDD induces CYP1A4 and CYP1A5 in chick liver and kidney and only CYP1A4, an enzyme lacking arachidonic acid epoxygenase activity, in myocardium and vascular endothelium [8].
• Glutathione depletion enhanced the effect of arsenite to decrease induction of CYP1A4 [4].
• Further, liver CYP1A4 and 1A5 mRNAs had the same half lives and were both superinduced by cycloheximide, whereas mRNA half lives differ for CYP1A1 and 1A2, and cycloheximide superinduces only CYP1A1 [10].

Other interactions of CYP1A4

• The developmental expression of CYP1A4-associated aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity and its association with expression of the Ah receptor had previously been characterized in chick embryo liver [7].
• Further, whereas TCDD induces only CYP1A1 and not CYP1A2 in extrahepatic organs, TCDD induces both CYP1A4 and 1A5 in chick kidney [10].

Analytical, diagnostic and therapeutic context of CYP1A4

• In situ hybridization study of tissue sections revealed induction of CYP1A4 in the abnormal liver tissue in which color change was not observed [6].
• At 100 nM, TCDD caused a significant increase in the number of apoptotic cells, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) assay, and induced the expression of the chicken cytochrome P450 1A4 (CYP1A4) mRNA, a hallmark of TCDD exposure [11].

References