Disease relevance of PPIG

• Genetic variability of the CYP 2D6 gene is not a risk factor for sporadic Parkinson's disease [1].
• In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis [2].
• Here, recombinant retroviruses were used to deliver six different CPA- or IFA-metabolizing human CYP genes to 9L gliosarcoma cells: 2B6, 2C8, 2C9, 2C18 (Met385 and Thr385 alleles), 2C19, and 3A4 [3].
• This report suggests an important physiological role of a CYP in the accumulation of uroporphyrin I arising from catalytic oxidative conversion of uroporphyrinogen I to uroporphyrin I in the periplasm of Escherichia coli cultured in the presence of 5-aminolevulinic acid [4].
• It might be a tougher challenge to obtain compounds specific for CYP D vs. other cyclophilins, and/or of small molecular weight, allowing brain penetration to make them suitable for treating neurodegenerative diseases [5].

Psychiatry related information on PPIG

• Variability of alimentary CYP expression may contribute to individual differences in susceptibility to carcinogens and/or drugs [6].

High impact information on PPIG

• Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics [7].
• However, as it is possible that human CYP 1A2 may also be inducible by these same chemicals (because of the possible presence of an ARE in this gene), the ultimate consequence of dietary treatment with chemicals that induce biotransformation enzymes via an ARE is uncertain [8].
• The role of a 150-kD SR-cyclophilin (NK-TR1) in monocyte differentiation was investigated [9].
• Association of the expression of an SR-cyclophilin with myeloid cell differentiation [9].
• This indicates that factors affecting CYP 2E1 metabolism exerted a greater role on production of 1,4-BQ than BO, presumably because of the second oxidation step from phenol to hydroquinone [10].

Chemical compound and disease context of PPIG

• CYP1A in TCDD toxicity and in physiology-with particular reference to CYP dependent arachidonic acid metabolism and other endogenous substrates [11].
• The effects of two CYP-derived metabolites of daidzein, 6,7,4'-trihydroxyisoflavone and 7,3',4'-trihydroxyisoflavone, were studied in the MCF-7 human breast cancer cell line at a concentration (50 microM) at which daidzein induces an antiproliferative response [12].
• Nicotine induces brain CYP enzymes: relevance to Parkinson's disease [13].
• Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite [14].
• Using genetically engineered Salmonella typhimurium expressing a human CYP, we found that CYP2A6 was involved in the metabolic activation of a variety of nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contained in tobacco smoke [15].

Biological context of PPIG

• SR-cyp might direct its effect via either alteration of protein folding/conformation or of protein-protein interaction and thus may add another control level of regulation of SR family proteins and modification of their functions [16].
• Only in late telophase is SRcyp recruited to the newly formed nuclei [17].
• We report here the identification of five Cdc2-type phosphorylation sites gathered in and around the moca domain of SRcyp, a human cyclophilin belonging to the Moca family [17].
• The cytochrome P450 3A7 (CYP3A7) is the most abundant CYP in human liver during fetal development and first months of postnatal age, playing an important role in the metabolism of endogenous hormones, drugs, differentiation factors, and potentially toxic and teratogenic substrates [18].
• The human P450IIB gene has been located to chromosome 19q12----19q13.2 using a probe derived from intron 5, and is close to the CYP 2A locus encoding cytochrome P450IIA2 [19].

Anatomical context of PPIG

• These results indicate that carcinogen activation by CYP enzymes expressed in the gastric mucosa may contribute to carcinogenesis of the stomach [20].
• A peptidyl-prolyl cis/trans-isomerase (cyclophilin G) in regulated secretory granules [21].
• Clarithromycin, ketoconazole, and fluconazole inhibited CYP-mediated metabolism of rifabutin in enterocyte microsomes equally or more potently than in liver microsomes but had no effect on cholinesterase activity [22].
• Microsomes enriched in each of these CYPs were obtained from commercial +/- lymphoblast cells that had been transfected with cDNA encoding the specific human CYP [23].
• Finally, the identification of mutant alleles of the P-450IID1 gene (CYP 2D) by restriction fragment length polymorphisms in lymphocyte DNA of poor metabolizers is presented [24].

Associations of PPIG with chemical compounds

• One explanation for the noted increase in the theophylline level is that metabolism occurs mainly by cytochrome P450 (CYP 1A2), an enzyme that is known to be inhibited with high concentrations of zafirlukast [25].
• Efavirenz induces the metabolism of co-administered drugs through the induction of CYP A4 [26].
• However, this possibility is at odds with previous clinical studies that showed that acute ethanol ingestion could protect against hepatotoxicity by inhibiting CYP-mediated acetaminophen oxidation [27].
• A combined mephenytoin, sparteine, and caffeine test performed before, during, and after multiple dosing of moclobemide showed changes in the metabolic indexes compatible with a reversible inhibition of oxidation by way of the corresponding CYP enzymes--CYP2C19, CYP2D6, and CYP1A2--during moclobemide treatment [28].
• The major pathways of arachidonic acid metabolism catalyzed by cytochrome P450 generate metabolites that are subdivided into two groups: the epoxyeicosatrienoic acids, formed by CYP epoxygenases, and the arachidonic acid derivatives that are hydroxylated at or near the omega-terminus by CYP omega-oxidases [29].

Other interactions of PPIG

• Over-expression of SR-cyclophilin, an interaction partner of nuclear pinin, releases SR family splicing factors from nuclear speckles [16].

Analytical, diagnostic and therapeutic context of PPIG

• CsA is cytoprotective in many cellular and animal models, but protection may result from either inhibition of the MPT through an interaction with CYP D or inhibition of calcineurin-mediated dephosphorylation of BAD through an interaction with CYP A [5].
• METHODS: Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours [30].
• Some transcripts, e.g., CYP 2A6/7, were not detected by either standard, non quantitative RT-PCR or the above methods, whereas others were barely quantifiable by StaRT-PCR, i.e., were present at 1-10 molecules/10(6) molecules of actin [31].
• CYP genotyping was performed by polymerase chain reaction (PCR) restriction fragment length polymorphism or allele-specific PCR [32].
• Metabolic activation of pradefovir to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was evaluated by using cDNA-expressed CYP isozymes in portal vein-cannulated rats following oral administration and in human liver microsomes [33].

References