Disease relevance of Cyp2c6

• Hepatocyte nuclear factor 3 is a major determinant of CYP2C6 promoter activity in hepatoma cells [1].

High impact information on Cyp2c6

• Cytochrome P450 2C6 (CYP2C6) is a developmentally regulated, constitutively expressed form of rat liver microsomal cytochrome P450 that in the liver of adult male rats is induced to a limited extent by phenobarbital [1].
• Immunohistochemical investigations of serial sections revealed that Naf also reduced expression of the altered phenotype when cytochrome P450-PB and pyruvate kinase (type L) were used as foci markers, but not when glutathione-S-transferase B (GST-B) was used [2].
• In normal parts of the liver PB induced DNA replication only in association with expression of P450-PB; both responses were restricted to the pericentral area of the liver lobule [3].
• We report here that (i) benzanthracene and PB induce P450 c mRNA in differentiated and dedifferentiated cells and (ii) dexamethasone and PB induce P450 b/e and/or P450 PB1 mRNAs in differentiated cells but not in dedifferentiated cells [4].
• However, the P-450-PB-dependent oxidation of ethanol can be masked under conditions in which .OH production is increased [5].

Biological context of Cyp2c6

• Evidence that the biotransformation of dapsone and monoacetyldapsone to their respective hydroxylamine metabolites in rat liver microsomes is mediated by cytochrome P450 2C6/2C11 and 3A1 [6].

Anatomical context of Cyp2c6

• These results suggest that P-450-PB does not catalyze the oxidation of .OH scavengers or promote the production of .OH, even at ratios of P-450/reductase approaching those found with intact microsomes and even in the presence of excess iron-EDTA, whereas ethanol is directly oxidized by P-450-PB, as are typical drug substrates [5].
• The major phenobarbital-inducible form of cytochrome P-450 (cytochrome P-450 PB) was purified to homogeneity from rat liver microsomes and rabbit antibodies prepared against the purified enzyme [7].
• Immunoreactive cytochrome P-450 PB was observed to decrease less rapidly than the spectrally detectable enzyme in the microsomal membranes [7].

Associations of Cyp2c6 with chemical compounds

• Rat hepatic cytochrome P-450 PB-1 is a prominent constitutive P-450 form whose levels increase approximately 2-3 fold upon phenobarbital administration [8].
• The product pattern was influenced by pretreatment with 3-methylcholanthrene, benzo(a)pyrene, phenobarbitone and Arochlor 1254 and by addition of anti-cytochrome P450-PB immunoglobulin [9].
• These results suggest the following: NDMA demethylation is catalyzed by PB-induced cytochrome P-450 species (P450-PB) and MC-induced cytochrome P-450 species (P448-MC) [10].
• This decrease at high P-450/reductase ratios could reflect tight coupling of reductase to P-450-PB, therefore decreasing electron transfer from reductase to ferric-EDTA, or could involve non-specific scavenging of .OH by P-450-PB [5].
• Phenobarbital and Aroclor 1254 pretreatments resulted in several-fold increases in immunoreactive cytochrome P-450 PB over control levels [7].

Other interactions of Cyp2c6

• The aim of this study was to examine the effect of oral administration of diallyl sulfide--a cytochrome P450 2E1 inhibitor and cimetidine--a cytochrome P450 2C6 and 2C11 inhibitor on rat serum concentration of phenacetin and its metabolite acetaminophen [11].
• 2-Acetylaminofluorene was found to increase the amount of cytochromes P-450b + e 10-fold and of cytochrome P-450d 3-fold, while there was a 54% increase in the level of cytochrome P-450 PB/PCN-E [12].
• Sodium dodecyl sulphate (SDS)-electrophoresis of microsomal proteins confirms the expected increase at 52 000 daltons (cytochrome P-450 PB) on PB-induction, at 56 000 daltons (cytochrome P-450MC) on MC-induction; after anaerobic incubation with [14C]CC14 the electrophoretic pattern is largely unchange [13].

Analytical, diagnostic and therapeutic context of Cyp2c6

• As indicators of adaptive responses we measured DNA synthesis cumulatively by infusion of [3H]thymidine for the entire period of PB treatment, and cytochrome P450-PB by immunocytochemistry on histological liver sections [3].
• Maximal increase in cytochrome P450-PB was 21-fold by morphometric analysis and 15-fold by ELISA [14].

References