ArticleBritish journal of pharmacology2011
Significantly reduced cytochrome P450 3A4 expression and activity in liver from humans with diabetes mellitus.
Article in British journal of pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05081765 (The Effect of Glucose Level and Diabetes Mellitus on the Plasma Minimum Steady-state Concentration Ctrough of Olaparib in Patients With Ovarian Cancer), which is not on this map. Cited by 49 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
The Effect of Glucose Level and Diabetes Mellitus on the Plasma Minimum Steady-state Concentration Ctrough of Olaparib in Patients With Ovarian Cancer
Who cites it
49 citing papers in PubMed, 133 citations in OpenAlex.
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Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
background and purposePatients 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
resultsMidazolam 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.
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