Potential role of drug metabolizing enzymes in chemotherapy-induced gastrointestinal toxicity and hepatotoxicity

ABSTRACT

Introduction

Toxicity of chemotherapy drugs is the leading cause of poor therapeutic outcome in many cancer patients. Gastrointestinal (GI) toxicity and hepatotoxicity are among the most common side effects of current chemotherapies. Emerging studies indicate that many chemotherapy-induced toxicities are driven by drug metabolism, but very few reviews summarize the role of drug metabolism in chemotherapy-induced GI toxicity and hepatotoxicity. In this review, we highlighted the importance of drug metabolizing enzymes (DMEs) in chemotherapy toxicity.

Areas covered

Our review demonstrated that altered activity of DMEs play important role in chemotherapy-induced GI toxicity and hepatotoxicity. Besides direct changes in catalytic activities, the transcription of DMEs is also affected by inflammation, cell-signaling pathways, and/or by drugs in cancer patients due to the disease etiology.

Expert opinion

More studies should focus on how DMEs are altered during chemotherapy treatment, and how such changes affect the metabolism of chemotherapy drug itself. This mutual interaction between chemotherapies and DMEs can lead to excessive exposure of parent drug or toxic metabolites which ultimately cause GI adverse effect.

KEYWORDS:

• Drug metabolizing enzymes
• chemotherapy
• reactive metabolites
• gastrointestinal toxicity
• hepatotoxicity

Article highlights

• Both intestinal and hepatic drug-metabolizing enzymes (DMEs) contribute to chemotherapy-induced gastrointestinal (GI) toxicity and hepatotoxicity.

• Altered activity of DME leads to excessive accumulation of parent drug or generation of reactive metabolites and consequently cause GI and hepatic toxicities.

• Alterations in DME activities depends on the regulation of DME gene expression and genetic polymorphism of DME.

• Gene expression of DMEs is governed by nuclear receptors, transcription factors that cross talk with inflammatory markers and other intracellular signaling pathways.

• Gut microbiota are involved in drug metabolism-induced toxicity by mediating reactive metabolism and by changing the expression of DMEs.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was in part supported by NIH grants R01HL129794, 1R01ES029382, 1P42 ES0327725, and Cancer Prevention Research Institute of Texas (CPRIT) RP190279.