High impact information on Cyp3a11

• Both PXR and CAR agonists profoundly stimulated bile acid-hydroxylating/detoxifying enzymes Cyp3a11 and Cyp2b10 [1].
• These trends were confirmed at the protein level by Western blot analysis using antibodies raised to Cyp2a, Cyp2b, and Cyp3a family members [2].
• The reduction of murine hepatic Cyp3a gene expression in tumor-bearing mice resulted in decreased Cyp3a protein expression and consequently a significant reduction in Cyp3a-mediated metabolism of midazolam [3].
• If fed in supranutritional dosages, especially for longer times, alpha-tocopherol induces Cyp3a11 to levels which might interfere with drug metabolism [4].
• In contrast, gamma-tocotrienol did not induce Cyp3a11 mRNA [4].

Biological context of Cyp3a11

• Consistent with the Q-PCR data, Western blots showed dose-dependent downregulation of Cyp3a only in females and induction of Cyp2a only in males [5].
• The mouse Cyp3a locus on chromosome 5 was analyzed by the use of bacterial artificial chromosomes [6].
• In conclusion, Fxr(-/-) mice detoxify accumulating bile acids in the liver by enhanced hydroxylation reactions probably catalyzed by Cyp3a11 [7].
• In addition, hepatic and renal gene expression levels of Cyp2b10 and Cyp3a11, and protein expression levels of putative renal bile acid-transporting proteins, were investigated [7].
• Gene structure of mouse Cyp3a11: evidence for an enhancer element within its 5' flanking sequences [8].

Anatomical context of Cyp3a11

• Treatment of hPXR-transduced cultured hepatocytes isolated from PXR-knockout mice with zearalenone induces the expression of Cyp3a11, the prototypical murine hepatic PXR-target gene [9].
• Cyp3a11 enzyme was expressed into CR119 cells which had been established as a cell line stably expressing NADPH-cytochrome P450 reductase cDNA of guinea pigs [10].
• No inhibition of SR 4233 reduction was seen with erythromycin or cyclosporin A which act as substrates/inhibitors for Cyp3a-type enzymes, but inhibition was seen with p-nitrophenol and tolbutamide which are substrates for Cyp2el- and Cyp2c-type enzymes, respectively (11% and 25% inhibition in induced microsomes) [11].
• The 6beta-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) based on the protein contents were 1.2- to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared to jvs/wt- or wt/wt-type mice [12].

Associations of Cyp3a11 with chemical compounds

• As expected, the mRNA levels of Cyp3a11, Cyp2b10, and Cyp1a2 were induced by a single dose of dexamethasone (100 mg/kg), phenobarbital (80 mg/kg), and 3-methylcholanthrene (80 mg/kg), respectively [13].
• Furthermore, hepatic microsomal activities for pentoxyresorufin O-dealkylation (PROD) and nifedipine oxidation, which are mainly mediated by Cyp2b and Cyp3a subfamily enzymes, respectively, were measured [14].
• Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for cytochrome P-450 (Cyp)7a1, Cyp3a11, and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition [15].
• In addition, all of six inducers, such as dexamethasone, 3-methylcholanthrene, phenobarbital, polychlorinated biphenyl, pregnenolone 16 alpha-carbonitrile, and rifampicin, increased the expression of the Cyp3a11 mRNA more extensively than that of Cyp3a13 [10].
• In summary, these results indicated that fluconazole, a triazole-containing conazole, clearly induced CYP2B and CYP3A families of isoforms in rat liver and Cyp2b and Cyp3a families of isoforms in mouse liver [16].

Enzymatic interactions of Cyp3a11

• SR 4233 itself inhibited benzphetamine N-demethylase, which is catalysed by Cyp2b-type enzymes but not erythromycin N-demethylase which is catalysed by Cyp3a-type isoforms [11].

Other interactions of Cyp3a11

• Cyp3a11 and Cyp2e1 mRNAs were not affected by any of the cytokines that were studied [13].
• Disruption of the aromatase gene caused an increase in the expression of Cyp3a11 protein, although the mRNA level remained unchanged [17].
• CAR/PXR provide directives for Cyp3a41 gene regulation differently from Cyp3a11 [18].
• Mouse cytochrome P450 (Cyp3a11): predominant expression in liver and capacity to activate aflatoxin B1 [10].
• The identity of 5' flanking sequences between Cyp3a16 and Cyp3a11 genes was about 69% [19].

Analytical, diagnostic and therapeutic context of Cyp3a11

• We have used a specific anti-PXR antibody in the Western blotting of mouse liver nuclear extracts to show that PXR is accumulated in the nucleus after treatment with 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (PCN), followed by an increase in Cyp3a11 mRNA [20].
• Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis [21].
• Peripheral administration of 2.5 microg LPS by intraperitoneal injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver [21].

References