Disease relevance of Cyp2c54

• Reduced hepatic cytochrome P-450 contents correlated with decreased abilities of liver homogenates to metabolically activate benzo [a]pyrene (CAS: 50-32-8) and N-acetyl-2-aminofluorene (CAS: 53-96-3), as scored in an Ames Salmonella typhimurium revertant assay [1].
• Inhibitors of the cytochrome P-450 enzymes block the secretagogue-induced release of corticotropin in mouse pituitary tumor cells [2].
• In mouse hepatoma cells, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the transcription rate of the CYP1A1 gene, which encodes a cytochrome P-450 enzyme [3].
• Interferon (IFN) and IFN inducers are known to depress hepatic microsomal cytochrome P-450 levels, and the liver toxicity of IFN was reported to be lethal in newborn mice [4].
• Administration of whole-cell diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) caused marked depression in the expression of mRNA for isozymes of cytochrome P-450 in the livers of endotoxin-responsive and nonresponsive mice [5].

Psychiatry related information on Cyp2c54

• Individual differences in the levels of cytochrome P450 expression would be expected, and are known, to give rise to profound differences in toxicological response [6].

High impact information on Cyp2c54

• As a family of structurally-related enzymes, cytochrome P450 (P450) monooxygenases exhibit paradoxical characteristics: although collectively the enzymes display a broad range of substrate specificities, individually they are characterized by a high degree of substrate and product selectivity [7].
• NADPH-cytochrome P450 reductase has been purified to apparent homogeneity and demonstrated to supply reducing equivalents from NADPH to cytochrome P450 (refs 5-7) [8].
• Detection of NADPH-cytochrome P450 reductase thus represents an indirect means of demonstrating the presence of cytochrome P450 [8].
• Although the role of cytochrome P450 in the central nervous system (CNS) is not known, it may include such different functions as metabolism of xenobiotics, aromatization of androgens to oestrogens and the formation of catecholoestrogens [8].
• Transgenesis with bacterial artificial chromosome (BAC) clones encompassing Rslcan-4 restores male-specific MUP (major urinary protein) expression to rsl mice, whereas a BAC containing Rslcan-9 rescues sex-specific expression of Slp and cytochrome P450 Cyp2d9 [9].

Chemical compound and disease context of Cyp2c54

• Role of hepatic cytochrome p450s in the pharmacokinetics and toxicity of cyclophosphamide: studies with the hepatic cytochrome p450 reductase null mouse [10].
• In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A [11].
• These results suggest that CYP17, in addition to its role in steroidogenesis and androgen formation, is present in germ cells where it is essential for sperm function, and deletion of one allele prevents genetic transmission of mutant and wild-type alleles causing infertility followed by change in sexual behavior due to androgen imbalance [12].
• The second most frequent clinical observation, renal toxicity, is described with respect to the involvement of prostaglandin synthase, N-deacetylase, cytochrome P450 and glutathione S-transferase [13].
• Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation [14].

Biological context of Cyp2c54

• Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals [15].
• CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed [15].
• Kinetics of depression and recovery of murine hepatic cytochrome P-450 levels after treatment with the interferon inducer polyriboinosinic-polyribocytidylic acid [1].
• These observations suggest that both MDR and cytochrome P-450 gene families are evolutionarily selected by the capacity of various xenobiotics to induce their own detoxification either through metabolism to hydrophilic derivatives by the cytochrome P-450 system or direct excretion from the cell by the MDR gene family [16].
• As assessed by a gel mobility shift assay, this receptor form did not bind to the xenobiotic response element (XRE) of the target gene cytochrome P-450 IA1 [17].

Anatomical context of Cyp2c54

• By difference spectrophotometry, the pellet was shown to contain cytochrome b5 and cytochrome P-450, hemeproteins that have been shown to participate in electron-transport reactions of endoplasmic reticulum and other membranous fractions of various tissues [18].
• The newly synthesized protein products are translocated into the microsomes, and their characterization by immunochemical analysis indicates that the sizes of the polypeptides expressed were indistinguishable from their cytochrome P-450 counterparts found in mammalian liver microsomes [19].
• Paradoxical transcriptional activation of rat liver cytochrome P-450 3A1 by dexamethasone and the antiglucocorticoid pregnenolone 16 alpha-carbonitrile: analysis by transient transfection into primary monolayer cultures of adult rat hepatocytes [20].
• A cytochrome P450-like gene, tentatively named P450CMEF, was amplified by a mixed oligonucleotide-primed amplification of cDNA from C3H mouse embryo fibroblast cells, designated 10T1/2, that had been treated with 7,12-dimethylbenz[a]anthracene (DMBA) or benz[a]anthracene (BA) [21].
• A procedure was developed for the per cell estimation of cytochrome P-450-dependent monooxygenase activities in cultures and whole cell suspensions of murine epidermal keratinocytes (MEKs) [22].

Associations of Cyp2c54 with chemical compounds

• Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR [15].
• The cytochrome P450 (CYP) gene products such as CYP3A and CYP2B are essential for the metabolism of steroid hormones and xenochemicals including prescription drugs [23].
• Cytochrome P-450 isoform d was induced by TCDD, isosafrole, phenothiazine, and AAF, while cytochrome P-450 isoform b was induced by phenobarbital, and to a lesser extent by isosafrole [16].
• These features were compared with those elicited by the activation of cyclophosphamide, which was transformed into cytotoxic metabolites by the cytochrome P450 form specifically induced by phenobarbital-type inducers [24].
• The amount of cytochrome P450 was increased per unit weight of microsomal protein and liver in mice fed BHA [25].

Physical interactions of Cyp2c54

• The ligand-activated aromatic hydrocarbon receptor (AHR) dimerizes with the AHR nuclear translocator (ARNT) to form a functional complex that transactivates expression of the cytochrome P-450 CYP1A1 gene and other genes in the dioxin-inducible [Ah] gene battery [26].
• The murine Ah complex represents a 'cluster' of genes controlling the induction of numerous cytochrome P-450-mediated monooxygenase 'activities' by polycyclic aromatic compounds [27].
• The effect of established inducers of microsomal P-450 caused complex changes in apparent rates of alpha-hydroxylation of NPYR which made interpretation of responses to inducer pretreatment difficult and suggested the participation of multiple cytochrome P-450 isozymes in the metabolism of NPYR [28].
• The metabolites catalyzed by cytochrome P-450 in vitro were bound exclusively to a 50-kDa microsomal protein, even in the presence of albumin [29].
• The influence of the major histocompatibility complex (H-2 in mouse) on induction of cytochrome P-450-dependent monooxygenase (P1-450) by the prototype polyaromatic hydrocarbon (PAH), beta-naphthoflavone, was investigated in C57BL/10 Sn (B10) recombinant congenic mice [30].

Enzymatic interactions of Cyp2c54

• Cytochrome P450 2A5-catalyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50% [31].
• The distribution of cytochromes P-450 that catalyze aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase were studied with monoclonal antibody (MAb) 1-7-1 which completely inhibits these activities of a purified 3-methylcholanthrene-induced rat liver cytochrome P-450 [32].

Regulatory relationships of Cyp2c54

• Müllerian inhibiting substance blocks the protein kinase A-induced expression of cytochrome p450 17alpha-hydroxylase/C(17-20) lyase mRNA in a mouse Leydig cell line independent of cAMP responsive element binding protein phosphorylation [33].
• AHR may directly or indirectly control levels of a cytochrome P450 that is responsible for catabolizing retinoic acid [34].
• Peroxisome proliferator activated receptor alpha regulates a male-specific cytochrome P450 in mouse liver [35].
• The cytochrome P450 steroid hydroxylases are coordinately regulated by steroidogenic factor 1 (SF-1), a protein expressed selectively in steroidogenic cells [36].
• Notably, LXR agonist treatment up-regulated CYP4A10 and CYP4A14 together with cytochrome P450 reductase, indicating a possible enhancement of microsomal lipid peroxidation [37].

Other interactions of Cyp2c54

• Finally, our results show that cytochrome p450 (CYP)-mediated RA metabolism prevents premature Stra8 expression in embryonic testes [38].
• Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent [39].
• A novel benz[a]anthracene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible cytochrome P-450 (P450EF), which is very active in polycyclic aromatic hydrocarbon metabolism, has been purified from C3H10T1/2 mouse embryo fibroblasts (Pottenger, L. H., Christou, M., and Jefcoate, C. R. (1991) Arch. Biochem. Biophys. 286, 488-497) [40].
• Here, we show that a mouse hepatic oxysterol 7alpha-hydroxylase is encoded by Cyp7b1, a cytochrome P450 cDNA originally isolated from the hippocampus [41].
• This sequence mediates transcriptional activation by a wide range of compounds including typical cytochrome P450 pan-inducers phenobarbital and metyrapone, as well as specific activators of the pregnane X receptor and the constitutive androstane receptor [42].

Analytical, diagnostic and therapeutic context of Cyp2c54

• The cDNA of cytochrome P450 (CYP) 2C43 was cloned from cynomolgus monkey liver by RT-PCR [43].
• None of the monoclonal antibodies cross-reacted with purified cytochromes P-450a, P-450b, P-450e, P-450f, P-450g, or P-450h or any other cytochrome P-450 in "Western blots" of liver microsomes from untreated or 3-methylcholanthrene-treated rats [44].
• The regulation of the novo synthesis of the microsomal cytochrome P-450 enzyme, P-450(17 alpha), was studied in mouse Leydig cell cultures [45].
• However, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in many cells, concomitant with severe hepatitis [46].
• Mouse antibodies raised against the cytochrome P-450 inhibited the reaction about 70% and reacted with the P-450cc24 in immunoblotting but did not react with other kinds of cytochrome P-450 in rat liver microsomes and mitochondria [47].

References