title: Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus.
abstract: OBJECTIVE
  Patients with diabetes mellitus require pharmacotherapy with numerous medications. However, the effect of diabetes on drug biotransformation is not well understood. Our goal was to investigate the effect of diabetes on liver cytochrome P450 3As, the most abundant phase I drug-metabolizing enzymes in humans.
  
  
  METHODS
  Human liver microsomal fractions (HLMs) were prepared from diabetic (n= 12) and demographically matched nondiabetic (n= 12) donors, genotyped for CYP3A4*1B and CYP3A5*3 polymorphisms. Cytochrome P450 3A4, 3A5 and 2E1 mRNA expression, protein level and enzymatic activity were compared between the two groups.
  
  
  RESULTS
  Midazolam 1'- or 4-hydroxylation and testosterone 6β-hydroxylation, catalyzed by P450 3A, were markedly reduced in diabetic HLMs, irrespective of genotype. Significantly lower P450 3A4 protein and comparable mRNA levels were observed in diabetic HLMs. In contrast, neither P450 3A5 protein level nor mRNA expression differed significantly between the two groups. Concurrently, we have observed increased P450 2E1 protein level and higher chlorzoxazone 6-hydroxylation activity in diabetic HLMs.
  
  
  CONCLUSIONS
  These studies indicate that diabetes is associated with a significant decrease in hepatic P450 3A4 enzymatic activity and protein level. This finding could be clinically relevant for diabetic patients who have additional comorbidities and are receiving multiple medications. To further characterize the effect of diabetes on P450 3A4 activity, a well-controlled clinical study in diabetic patients is warranted.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dostalek
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
mesh_terms: D015153:Blotting, Western; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000201:enzymology*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human