Cited by 54Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

Chronic Inflammatory Status Observed in Patients with Type 2 Diabetes Induces Modulation of Cytochrome P450 Expression and Activity

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Darakjian, Lucy, Deodhar, Malavika, Turgeon, Jacques, Michaud, Veronique·2021·International Journal of Molecular Sciences

Abstract

Diabetes mellitus is a metabolic disease that causes a hyperglycemic status which leads, over time, to serious damage to the heart, blood vessels, eyes, kidneys and nerves. The most frequent form of diabetes is type 2 diabetes mellitus (T2DM) which is often part of a metabolic syndrome (hyperglycaemia, hypertension, hypercholesterolemia, abdominal obesity) that usually requires the use of several medications from different drug classes to bring each of these conditions under control. T2DM is associated with an increase in inflammatory markers such as interleukin-6 (IL-6) and the tumor necrosis factor alpha (TNF-α). Higher levels of IL-6 and TNF-α are associated with a downregulation of several drug metabolizing enzymes, especially the cytochrome P450 (P450) isoforms CYP3As and CYP2C19. A decrease in these P450 isoenzymes may lead to unexpected rise in plasma levels of substrates of these enzymes. It could also give rise to a mismatch between the genotypes determined for these enzymes, the predicted phenotypes based on these genotypes and the phenotypes observed clinically. This phenomenon is described as phenoconversion. Phenoconversion typically results from either a disease (such as T2DM) or concomitant administration of medications inducing or inhibiting (including competitive or non-competitive inhibition) a P450 isoenzyme used by other substrates for their elimination. Phenoconversion could have a significant impact on drug effects and genotypic-focused clinical outcomes. As the aging population is exposed to polypharmacy along with inflammatory comorbidities, consideration of phenoconversion related to drug metabolizing enzymes is of importance when applying pharmacogenomic results and establishing personalized and more precise drug regimens.

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Research works printed but not linked: 2

  1. [1]Organization WH Diabetes Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860345/pdf/nihms-779960.pdf (accessed on 1 April 2021)
  2. [18]American Diabetes Association Standards of Medical Care in Diabetesd Diabetes Care 2019 42 S90 S102 30559235

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Authors
Darakjian, L., Deodhar, M., Turgeon, J., & Michaud, V.
Affiliations
  • Tabula Rasa HealthCare (United States) (US)
  • Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-05-07
Volume
22
Issue
9
Pages
4967
ISSN
1422-0067 (ISSN-L)
OpenAlex
W3158869533
Cited by
53
References
155
Citations by year
2026: 5 · 2025: 9 · 2024: 7 · 2023: 12 · 2022: 13 · 2021: 7
FWCI
1.72
Type
journal article
Language
en
Open access
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
type 2 diabetes, chronic inflammation, cytochrome P450, CYP3A4/5, CYP2C19, phenoconversion, drug-metabolizing enzymes, interleukin-6, TNF-α, metabolic syndrome, polypharmacy, pharmacogenomics, drug interactions
MeSH terms
Animals, Chronic Disease, Cytochrome P-450 Enzyme System, Diabetes Mellitus, Type 2, Humans, Inflammation, Insulin, Models, Biological

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