Fig. 1.

Scheme of the inhibitory influence of inflammation on drug-metabolizing enzyme and transporter (DMET) activity, leading to overexposure to drugs that are DMET substrates and have a narrow therapeutic index. Pathogen-associated molecular patterns or damage-associated molecular patterns stimulate pro-inflammatory cytokine pathways, leading to transcriptional and post-transcriptional changes in DMETs. Transcriptional mechanisms involve NF-κB activation, which inhibits the heterodimerization of nuclear retinoid x receptor (RXR)-α to other constitutive nuclear receptors (NR) (1), thus inhibiting DMET transcription (2) (under the magnifying glass). Non transcriptional mechanisms involve the direct inhibition of DMET by NO and the induction of proteasome-dependent CYP3A4 inhibition by NO. Finally, epigenetic changes, such as DNA methylation in response to inflammation, contribute to reduced DMET activity (under the magnifying glass).

NR: nuclear receptor, including the peroxisome proliferator activating receptor, pregnane X receptor, retinoid X receptor-α, and constitutive androstane receptor.

Solid lines indicate activation and dotted lines indicate inhibition.