Influence of serum inflammatory cytokines on cytochrome P450 drug metabolising activity during breast cancer chemotherapy: a patient feasibility study

Abstract

Individual response to chemotherapy in patients with breast cancer is variable. Obesity and exercise are associated with better and worse outcomes, respectively, and it is known that both impact the systemic cytokine milieu. Cytochrome P450 (CYP) enzymes are responsible for the metabolism of many chemotherapy agents, and CYP enzyme activity has been shown to be modified by inflammatory cytokines in vitro and in vivo. Cytokine-associated changes in CYP metabolism may alter chemotherapy exposure, potentially affecting treatment response and patient survival. Therefore, better understanding of these biological relationships is required. This exploratory single arm open label trial investigated changes in in vivo CYP activity in twelve women treated for stage II or III breast cancer, and demonstrated for the first time the feasibility and safety of utilising the Inje phenotyping cocktail to measure CYP activity in cancer patients receiving chemotherapy. Relative CYP activity varied between participants, particularly for CYP2C9 and CYP2D6, and changes in serum concentrations of the inflammatory cytokine monocyte chemoattractant protein 1 inversely correlated to CYP3A4 activity during chemotherapy. Future use of phenotyping cocktails in a clinical oncology setting may help guide drug dosing and improve chemotherapy outcomes.Clinical Trial Registration: Trial was retrospectively registered to the Australia New Zealand Clinical Trial Registry (ANZCTR). ACTRN12620000832976, 21 Aug 2020, https://www.anzctr.org.au/ACTRN12620000832976.aspx.

Evaluation of important human CYP450 isoforms and P‐glycoprotein phenotype changes and genotype in type 2 diabetic patients, before and after intensifying treatment regimen using Geneva cocktail

“…Expression of the cytochromes 1A2, 2C9 and 2C19 enzymes is sensitive to the inflammatory mediators in higher concentrations of cytokines 17–19 . More importantly, there are interpersonal differences in response to inflammation, in which the clinical outcome of inflammation‐induced phenoconversion may vary significantly among individuals and different metabolic pathways through which drugs are metabolized 20–22 …”

The Potential Application of Extracellular Vesicles from Liquid Biopsies for Determination of Pharmacogene Expression

“…Indeed, variation in drug response or mRNA expression within a specific genotype are often due to phenoconversion, a mismatch between the genotype and predicted phenotype [40]. This mismatch is a result of non-genetic factors such as weight, gender, age and alcohol consumption but could also be disease related for instance infections that lead to the release of cytokines suppressing expression and/or activity of CYP enzymes [40,41].…”

Evaluation of the inhibitory potentials of selected compounds from Costus spicatus (Jacq.) rhizome towards enzymes associated with insulin resistance in polycystic ovarian syndrome: an in silico study

“…Cytochrome P450 (CYP) enzymes are responsible for the metabolism of most clinically used drugs [27]. Out of over 50 known CYP enzymes, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize about 90% of drugs [28].…”