Disease relevance of CYP3A5

• CYP3A5 is upregulated by glucocorticoids via the glucocorticoid receptor (GR) in lung adenocarcinoma derived A549 cells [1].
• We found no association of CYP3A5 genotypes with prostate cancer or disease severity [2].
• RESULTS: The single tacrolimus dose per body weight was significantly higher in CYP3A5 *1 carriers than CYP3A5 *3/*3 carriers (0.143+/-0.050 vs. 0.078+/-0.031 mg/kg, P<0.001) [3].
• We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population [4].
• CYP3A5 mRNA expression was significantly higher in adenoma in comparison to normal tissue of patients with adenoma (approximately 48%) [5].
• This finding supports an endogenous function of CYP3A5 related to the metabolism of intra-prostatic androgens and cell growth, and that polymorphisms affecting CYP3A5 activity may result in altered prostate cancer risk and aggressiveness [6].

High impact information on CYP3A5

• Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people [7].
• The three-dimensional displacement, or pharmacophore, of chemical features in space that are derived from inhibition data have produced pharmacophores for CYP3A4, CYP3A5 and CYP3A7, and provide new insights into ligand binding for each enzyme [8].
• The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (P =.002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P =.02 and.03, respectively) [9].
• CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women [10].
• METHODS: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial [10].

Chemical compound and disease context of CYP3A5

• To begin the study of the molecular events in the glucocorticoid regulation of CYP3A5, we fused 5' sequences of CYP3A5 to the chloramphenicol acetyltransferase gene in a vector that contains the herpes simplex virus thymidine kinase promoter [11].
• CYP3A5 is the major CYP3A form in the human lung, and it is inducible by dexamethasone in the human A549 lung adenocarcinoma cell line [12].
• The postmortem/in vivo data provided the first scientific evidence that CYP3A5 is involved in the fentanyl metabolism, and homozygous CYP3A5 *3 causes impaired metabolism of fentanyl, and genotyping CYP3A4*1B and 3A5*3 variants may help to certify the fentanyl toxicity [13].
• This study was performed to evaluate variability in the pharmacokinetics of bepridil in 38 Japanese patients with arrhythmias, and to investigate the effects of aprindine as well as CYP2D6 and CYP3A5 polymorphisms on the oral clearance of bepridil [14].

Biological context of CYP3A5

• In this manner, induction of CYP3A5 may contribute to the overall importance of this P450 in drug metabolism and drug interactions [15].
• Taken together, studies here revealed the presence of a functional ER6 motif in the CYP3A5 promoter located -100 bp upstream from the transcription start site, suggesting that CYP3A5 is inducible by mechanisms similar to those involved in CYP3A4 induction [15].
• Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing [16].
• The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4 [17].
• Sequencing data indicated that plasmids in 58 of 59 recombinant positive colonies contained an insert with a sequence identical to that present in CYP3A7 cDNA and the plasmid of only one colony contained an insert with a sequence identical to that present in CYP3A5 cDNA [18].

Anatomical context of CYP3A5

• In one human hepatocyte culture that contained the polymorphically expressed CYP3A5 in addition to the more widely expressed CYP3A4, only CYP3A4 was induced by cyclophosphamide, ifosfamide, and rifampin [19].
• This was confirmed at the protein level by immunoblot comparison of small intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 proteins [20].
• We report that treatment of Caco-2 cells with 1 alpha,25-dihydroxyvitamin D3, beginning at confluence, results in a dose- and duration-dependent increase in CYP3A4 mRNA and protein, with little apparent effect on the expression of CYP3A5 or CYP3A7 [21].
• These results suggest that CYP1A1 and CYP1B1 are differentially regulated in human pulmonary epithelial cells and give the first indication of the induction of CYP3A5 by glucocorticoids in human lung cells [22].
• We conclude that CYP3A4 and CYP3A5 are present throughout the human digestive tract and that differences in the expression of these enzymes may account for inter-organ differences in the metabolism of CYP3A substrates [23].

Associations of CYP3A5 with chemical compounds

• Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7-54.6 L/h] and 19.3 L/h [95% CI, 11.2-27.4 L/h], respectively; P = .03) [16].
• CYP3A5 was induced 8-fold by dexamethasone and 11-fold by phenobarbital [22].
• Notably, CYP3A5 had an unusually high ratio of 4- to 2-hydroxylation of 17beta-estradiol or estrone (0.53 or 1.26, respectively) [24].
• In the absence of CYP3A5, a significant correlation was observed between 3-methoxymorphinan formation and the sample's erythromycin N-demethylase activity (r2 = 0.94, N = 12, P < 0.01), testosterone 6 beta-hydroxylase activity (r2 = 0.96, N = 7, P < 0.01) and relative immunoquantified levels of CYP3A4 (r2 = 0.96, N = 12, P < 0.01) [25].
• The results showed that CYP3A4 and CYP3A5 contribute >95% to both testosterone 6beta-hydroxylation and diazepam 3-hydroxylation and 52 to 73% to diazepam N-demethylation, respectively [26].
• Patients with the intestinal CYP3A5*1 genotype tended to require a higher dose of tacrolimus compared to the other group with the same hepatic CYP3A5 genotype [27].

Regulatory relationships of CYP3A5

• CYP3A7 expression was thus higher than that of the polymorphically expressed CYP3A5 in adult human livers, based on a comparison with a previous study using our CYP3A5 peptide-specific antibody [28].
• CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days [29].
• The CYP3A5 recombinant protein expressed in Escherichia coli using the pCWOri expression vector was purified to an almost electrophoretically homogeneous state with a specific content of 4.4 nmol of P450/mg of protein [30].
• Both enzymes also catalyzed 6 beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione, although hPCN1 exhibited several-fold higher expressed activity than hPCN3 [31].

Other interactions of CYP3A5

• Hepatic expression of PXR correlated with that of CYP3A5 mRNA levels in a bank of liver samples [15].
• PGC1alpha also showed a moderate activating effect on CYP3A4, CYP3A5, and CYP2D6 [32].
• CYP3A4 and CYP3A5 had their highest mRNA expression in the duodenum (P < 0.001 and P < 0.000 001, respectively) and CYP2E1 in the stomach (P < 0.01) [33].
• On the other hand, the expression levels of CYP2C9 and CYP3A5 mRNA showed small and variable changes in each donor even at a high concentration (50 microM) of NO-1886 [34].
• CYP3A5 and CYP4B1 transcripts were found only in samples from premenopausal women [35].

Analytical, diagnostic and therapeutic context of CYP3A5

• Both CYP3A4 and CYP3A5 mRNA were detectable in all regions of the digestive tract using the polymerase chain reaction (PCR); however, only CYP3A4 could be detected by Northern blot analysis [23].
• The aim of the current case-control study was to compare the frequency of CYP2D6 and CYP3A5 polymorphisms, as well as one CYP3A4 promoter variant in BEN patients and controls in order to investigate a possible association between individual genetic variations in these genes and susceptibility to BEN [36].
• Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid was quantified by real-time reverse transcriptase-polymerase chain reaction [37].
• The correlation between CYP3A5 content, determined through immunoblotting, and 1'-OHM formation rate was high (r2 = 0.84, 24 experiments) [38].
• Compared with CYP3A5 nonexpressers, subjects with at least 1 CYP3A5*1 allele (CYP3A5 expressers) had greater inhibition of intestinal CYP3A activity after treatment with clarithromycin [37].

References