Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P450 3A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small mole-cules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.

Objective To investigate the clinical value of susceptibility weighted imaging (SWI)combined with three dimensional pseudo continuous arterial spin labeling (3D-PCASL)on the prognosis analysis of acute cerebral infarction.Methods Thirty cases with acute cerebral infarction (< 72 h)underwent conventional MRI,MRA,3D-PCASL and SWI.NIHSS scores were performed at the time of examination and 3 months later.The correlation between the collateral blood vessels,regional cerebral blood flow (rCBF)detected by combination of SWI and 3D-PCASL with clinical prognosis were analyzed.Results Twenty-three cases showed collateral blood vessels in the lesions with 1 grade in 14,and 2 grade in 9.The average rCBFs in grade 0,1,2 infarction areas were (22.69±11.94)mL·100 g-1 ·min-1 ,(25.10±16.55)mL·100 g-1 ·min-1 and (33.04±24.24)mL·100 g-1 ·min-1 ,respectively.Collateral blood vessels,rCBF were positive correlated with the NIHSS scores (r=0.989,P< 0.01).18 cases showed multiple vessels around the lesions. The average rCBFs in the infarction area with or not with periphery collateral blood vessles were (28.33±24.24)mL·100 g-1 ·min-1 and (22.69±11.94)mL·100 g-1 ·min-1 ,respectively.There was a positive correlation between rCBF and NIHSS scores (r=0.897,P<0.01). Of 30 cases of acute cerebral infarction,the average CBFs in the infarct areas and the contralateral mirror areas were (26.92±18.22)mL·100 g-1 · min-1 and (34.22±12.37)mL·100 g-1 ·min-1 .There was significant difference (t=8.093,P<0.01).Conclusion The combination of SWI and 3D-PCASL can display the collateral blood vessels in the lesions and soft meninges,and provide the quantitative analysis of rCBF,which has important clinical significance for prediction of the prognosis of acute cerebral infarction.

Objective To explore the diagnostic value of helical CT,fluid attenuated inversion recovery(FLAIR),magnetic resonance angiography (MRA)and susceptibility weighted imaging (SWI)at 3.0T MR for acute ischemic stroke (AIS).Methods 48 cases of AIS(<72 h)underwent conventional CT,MRI,MRA and SWI.The correlations between hyperdense middle cerebral artery sign (HMCAS),proximal hyperintense vessel sign(HVS),magnetic sensitive spatially-integrated susceptibility vessel sign(SVS),vascular dot middle cerebral artery sign(DMCAS),distal HVS and collateral circulation of the blood vessels surrounding leptomeninges expansion degree were analyzed.Results In 48 AIS cases,HMCAS were showed in 18(37.5%),DMCAS 12(25.0%),proximal HVS 33(68.7%), distal HVS 40(83.3%),SVS 43(89.6%)and surrounding soft meningeal vascular 39(81.2%).The difference between spatially-integrated SVS and HVS was statistically significant (P<0.05);For HVS and HMCAS responsibility blood vessels at the bottom,the difference was statistically significant(P<0.01).For pia mater lesions around the blood vessel and distal HVS display degree,the responsibility of the blood vessels was high consistency(P=0.789).The difference between MCA distal HVS and DMCAS was statistically significant (P<0.01).Conclusion It has obvious consistency for SVS,proximal HVS and HMCAS of MCA on the responsibility of AIS.SWI is better than FLAIR and CT.It has obvious statistical sighificance between DMCAS,HVS and surrounding leptomenings vasodilatiov.

The pregnane X receptor (PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters. Several protein isoforms of PXR exist, and they have differential transcriptional activity upon target genes; transcript variants 3 (PXR3) and 4 (PXR4) do not induce target gene expression, whereas transcript variants 1 (PXR1) and 2 (PXR2) respond to agonist by activating target gene expression. PXR protein variants also display differences in protein-protein interactions; PXR1 interacts with p53, whereas PXR3 does not. Furthermore, the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants, and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues.andmRNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed. Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis, therapeutic response, and the development of toxicity.

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.