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Genetic variations and epigenetic modulations in CYP genes: Implications in NSAID-treatment of arthritis patients

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Abstract

Drugs show specific pharmacodynamic properties and a plethora of adverse drug reactions depending on the genetic makeup of their users. Pharmacogenomics explains the variations of effects of drugs in humans depending on their race, ethnicity, age and gender. It has been extensively reported in the literature that variations in drug metabolism is associated with genetic polymorphism. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for pain management in arthritis. Cytochrome P450 (CYP) 2C9 is responsible for the metabolism of a wide range of drugs including the NSAIDs. The gene encoding for this enzyme is found in different polymorphic forms. People with CYP variants, CYP2C9*2 and CYP2C9*3 have been found to exhibit marked differences in NSAID metabolism and clearance compared to individuals with the wild type CYP gene (CYP2C9*1). There are several reports indicating epigenetic regulation of the CYP promoter that influences expression and functionality of this enzyme complex. Complications like adverse drug reactions involving gastro-intestinal bleeding are often fatal in NSAID treated patients with genetic polymorphism. In this review, complications associated with the use of NSAIDs and CYP polymorphism including drugs that are under investigation to bypass CYP polymorphism-linked adverse drug reactions, are discussed.

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Abbreviations

AS:

Ankylosing spondylitis

ASA:

Acetyl salicylic acid

AUGITB:

Acute upper gastro-intestinal tract bleeding

CAR:

Constitutive androstane receptor

CDC:

Centers for disease control and prevention

COX:

Cyclooxygenase

CPIC:

Clinical pharmacogenetics implentation consortium

CV:

Cardiovascular

CYP:

Cytochrome P450

DNMTs:

DNA methyltransferase

GA:

Gouty arthritis

mPGES-1:

Microsomal prostaglandin E2 synthase-1

hPH:

Human primary hepatocytes

HNF4:

Hepatocyte nuclear factor 4

mg/d:

Milligrams per day

MC:

Mediator complex

MED25:

Mediator complex subunit 25

NF-kB:

Nuclear factor-kB

NO-NSAIDS:

Nitric oxide producing NSAID

NSAID:

Nonsteroidal anti-inflammatory drugs

NIADR:

NSAID-induced adverse drug reactions

NR:

Nuclear receptor

OA:

Osteoarthritis

PA:

Psoriatic arthritis

RA:

Rheumatoid arthritis

PXR:

Pregnane receptor

SJS:

Stevens-Johnson Syndrome

TEN:

Toxic epidermal necrolysis

RDC:

Reduced drug clearance

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Acknowledgements

Natural Sciences and Engineering Research Council of Canada is acknowledged for support (NSERC, application number RGPIN-2020-05786). The authors would also like to acknowledge the support from Department of Higher Education, Government of West Bengal, India

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Natural Sciences and Engineering Research Council of Canada (NSERC, application number RGPIN-2020–05786).

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Authors and Affiliations

  1. Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal, 700126, India

    Shalini Roy Chowdhury & Oindrilla Dutta Gupta

  2. Department of Biochemistry, School of Life Science and Biotechnology, Adamas University, Kolkata, West Bengal, 700126, India

    Arnab Kumar Ghosh

  3. Department of Chemistry, Government General Degree College, Paschim Medinipur, Kharagpur, II-721149, West Bengal, India

    Partha Sarathi Singha

  4. Department of Physiology, Government General Degree College, Paschim Medinipur, Kharagpur, II-721149, West Bengal, India

    Syed Benazir Firdaus

  5. Department of Pharmacology and Physiology, Université de Sherbrooke, Sherbrooke, QC, Canada

    Klaus Klarskov

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KK and SBF conceived and planned the review. SRC, ODG, AKG and SBF drafted the manuscript. KK and PSS did critical revision of the article. KK and SBF finally approved the version to be published.

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Chowdhury, S.R., Gupta, O.D., Ghosh, A.K. et al. Genetic variations and epigenetic modulations in CYP genes: Implications in NSAID-treatment of arthritis patients. Nucleus 64, 331–342 (2021). https://doi.org/10.1007/s13237-021-00373-0

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