Disease relevance of CYP3A

• We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL) [1].
• CONCLUSION: The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway [2].
• BACKGROUND & AIMS: Comorbidities associated with nonalcoholic fatty liver often require therapy with medications (eg, statins) metabolized by cytochrome P-450 3A (CYP3A) [3].
• As expected, hepatic CYP3A activity was reduced in cirrhosis [4].
• We conclude that the furano diterpenoids of germander are activated by CYP3A into electrophilic metabolites that deplete glutathione and cytoskeleton-associated protein thiols and form plasma membrane blebs [5].

Psychiatry related information on CYP3A

• Attention should be given to immune toxicity associated with CYP3A4 autoantibodies and cases of alcohol abuse that are accompanied by exposure to drugs and substances that are CYP3A substrates [6].
• CONCLUSIONS: Individual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure [7].

High impact information on CYP3A

• CYP3A genetics in drug metabolism [8].
• In vitro and in vivo drug interactions involving human CYP3A [9].
• 3H-AFB1 was instilled into a loop of small bowel of untreated rats and rats pretreated with the CYP3A inducer dexamethasone during vivisection [10].
• CONCLUSIONS: Intracellular AFB1 adducts are formed in the small intestine, and this reflects, at least in part, the catalytic activity of CYP3A enzymes [10].
• RESULTS: In both rats and humans, AFB1-adducts were detected exclusively in mature enterocytes in a pattern similar to the distribution of CYP3A enzymes [10].

Chemical compound and disease context of CYP3A

• Female rat hepatocytes, which poorly express CYP3A, exhibited little toxicity, unless the animals were treated with dexamethasone [5].
• Pretreatment of male rats with troleandomycin, an inhibitor of cytochrome P450 3A (CYP3A), slowed the depletion of glutathione and decreased toxicity, whereas dexamethasone, an inducer of CYP3A, had opposite effects [5].
• Induction of cytochrome P450 3A (CYP3A) has been suggested as a mechanism of action of ursodeoxycholic acid (UDCA) in cholestasis [11].
• Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol [12].
• Alfentanil effect (miosis) is a surrogate for plasma alfentanil concentrations, and alfentanil effect kinetics may be a suitable noninvasive probe for hepatic CYP3A [13].

Biological context of CYP3A

• Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days) [2].
• Teucrin A (TA) was found responsible for the hepatotoxicity via metabolic activation by CYP3A [14].
• METHODS: We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls [2].
• Cyclosporine is a substrate of cytochrome P-450 3A (CYP3A) subfamily of enzymes and characterized by a narrow therapeutic range with wide interindividual variation in pharmacokinetics [15].
• A few single-nucleotide polymorphisms detected in CYP3A genes have been shown to correlate significantly with the CYP3A protein expression and activity [15].

Anatomical context of CYP3A

• For differentiation of CYP3A4 and -3A7 levels, dehydroepiandrosterone metabolite patterns for expressed CYP3A forms were characterized and used for simultaneous quantitation of protein levels within liver microsome samples [16].
• Valpromide (0.5-2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression.Conclusions:Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver [17].
• The increased formation of secondary and tertiary metabolites in rat microsomes with high expression of CYP3A1/2 compared with uninduced rats confirmed the role of CYP3A in taxane metabolism [18].
• In conclusion, the present study suggests that it is possible to predict quantitatively the CYP3A enzyme induction from hepatocyte data [19].
• In comparison with the gut mucosa, in hepatocytes the spatial sequence of CYP3A and P-glycoprotein is reversed, resulting in different effects when the activity of one or both are changed [20].

Associations of CYP3A with chemical compounds

• Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5 [21].
• Thus studies were undertaken to determine the effect of tariquidar, a potent P-glycoprotein inhibitor that does not affect CYP3A activity, on the ERBT and on the CYP3A-mediated metabolism of midazolam, a non-P-glycoprotein substrate [22].
• Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy [23].
• METHODS: In study 1 all 15 healthy volunteers received single oral doses of midazolam (7.5 mg), as a CYP3A probe, and gefitinib (500 mg), separated by an appropriate washout period [7].
• Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform [24].

Regulatory relationships of CYP3A

• CONCLUSIONS: Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A [25].

Other interactions of CYP3A

• The gene CYP3 encoding P450pcn1 (nifedipine oxidase) is tightly linked to the gene COL1A2 encoding collagen type 1 alpha on 7q21-q22.1 [26].
• For example, species-specific gene duplications and gene conversion events in the CYP2 and CYP3 families have produced different isoforms in rats and humans since the species division over 80 million years ago [27].
• We suggest that, under conditions when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool, the contribution of CYP3A5 to the clearance of some drugs may be an important source of interindividual variability [28].
• 5. Induction of the CYP3 gene family by the glucocorticoid dexamethasone appears to involve the glucocorticoid receptor, but this receptor is not apparently required for induction by metapyrone and a complete molecular understanding of the induction processes is lacking at present [29].
• 1. A structural model of CYP3A4 is reported on the basis of a novel amino acid sequence alignment between the CYP3 family and CYP102, a bacterial P450 of known crystal structure [30].

Analytical, diagnostic and therapeutic context of CYP3A

• The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients [15].
• The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays.Key results:Valproic acid (0.5-2.0 mM) induced P-gp expression and function up to 4-fold in vitro [17].
• These results indicate that, although induction of CYP3A and 2B in cryopreserved SHs is inferior to that in subcultured ones, SHs can maintain the expression and activities of P450s after long-term cryopreservation [31].
• The increase of 6beta-TH activity (CYP3A-linked), one of the most representative isoforms in humans, was sustained in liver and kidney by means of Western immunoblotting, using rabbit polyclonal antibodies anti CYP3A1/2 [32].
• Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients [33].

References