Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics

Abstract

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

Osteopontin deficiency leads to the resolution of prostatic fibrosis and inflammation

“…72 CYB2B6 was shown to be expressed in prostate epithelial cells and suppressed in prostate cancer cells, its downregulation correlates with poor prognosis and its overexpression inhibits proliferation in LNCaP prostate cancer cells. 73 Inflammatory cytokines, especially IL-6, generally downregulate the expression of cytochrome P450 enzymes 74 , but how their suppression contributes to inflammation and fibrosis in the prostate is unclear and needs further investigation.…”

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

“…Other studies have demonstrated a correlation between P450 isoform expression levels and cytokines levels [ 56 , 57 , 58 ]. An in vitro study examined the effect of five pro-inflammatory cytokines IL-1β, IL-4, IL-6, TNF-α and interferon gamma (IFN-γ) on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A in primary human hepatocyte cultures [ 59 ].…”

“…Drug metabolizing enzymes such as P450s are regulated at transcriptional and post-transcriptional levels [ 55 ]. Regulation of P450 mRNA levels by factors such as transcription factors such as the nuclear receptor pregnane X receptor (PXR) and its dimerization with retinoid X receptor (RXR), is responsible for the observed downregulation of P450 enzymes under inflammatory conditions [ 56 ]. Furthermore, it has been suggested that transcription factor nuclear factor-kappa B (NF-κB) could control the expression of several P450 enzymes through its interaction with the promotor region of their genes [ 56 ] ( Figure 1 ).…”

Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

“…Inflammation-induced dysregulation patterns of UGTs are probably pathology-dependent, tissue-specific and isoform-heterogeneous. The direction and extent of change depend on the type of inflammation, cytokine spectrum and time course (36,37). In rat colitis model, the expression and activity of hepatic UGTs were significantly down-regulated except for the up-regulation of UGT1A7, but those in small intestine were unaffected (36).…”