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Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus
Author(s) -
Dostalek Miroslav,
Court Michael H.,
Yan Bingfang,
Akhlaghi Fatemeh
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01270.x
Subject(s) - cyp3a4 , cytochrome p450 , diabetes mellitus , cyp2e1 , chlorzoxazone , medicine , endocrinology , cyp1a2 , pharmacology , microsome , chemistry , enzyme , metabolism , biochemistry
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.