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Review
. 2020 Nov;16(11):1109-1124.
doi: 10.1080/17425255.2020.1815705. Epub 2020 Sep 2.

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

Gabriel Tao  1 , Junqing Huang  2 , Bhagavatula Moorthy  3 , Cathryn Wang  4 , Ming Hu  1 , Song Gao  5 , Romi Ghose  1
Affiliations
Review

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

Gabriel Tao et al. Expert Opin Drug Metab Toxicol. 2020 Nov.

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; gastrointestinal toxicity; hepatotoxicity; reactive metabolites.

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Figures

Fig 1.
Fig 1.
Altered intestinal and/or hepatic drug metabolism mediates chemotherapy-induced toxicity
Fig 2.
Fig 2.. Regulation of DMEs expression by diseases and toxicity
Abbreviations: TNF-α: tumor necrosis factor-α, IL-6: interleukin-6; TIRAP: Toll/interleukin-1-receptor-domain-containing adaptor protein, TRIF: TIR-domain-containing adapter-inducing interferon-β, JNK: c-Jun N-terminal kinases, NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells, IKK: IκB kinase, GSK3β: Glycogen synthase kinase 3β, APC: Adenomatous polyposis coli protein, PXR: Pregnane X receptor, CAR: Constitutive androstane receptor, LXR: Liver X receptor, AhR: Aryl hydrocarbon receptor, RXR: Retinoid X receptor.
Fig 3.
Fig 3.
Chemotherapy drugs causing GI toxicity or hepatotoxicity due to reactive metabolites
See this image and copyright information in PMC

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