Regulation of cytochrome P450 enzyme activity and expression by nitric oxide in the context of inflammatory disease

Abstract

Many hepatic cytochrome P450 enzymes and their associated drug metabolizing activities are down-regulated in disease states, and much of this has been associated with inflammatory cytokines and their signaling pathways. One such pathway is the induction of inducible nitric oxide synthase (NOS2) and generation of nitric oxide (NO) in many tissues and cells including the liver and hepatocytes. Experiments in the 1990s demonstrated that NO could bind to and inhibit P450 enzymes, and suggested that inhibition of NOS could attenuate, and NO generation could mimic, the down-regulation by inflammatory stimuli of not only P450 catalytic activities but also of mRNA expression and protein levels of certain P450 enzymes. This review will summarize and examine the evidence that NO functionally inhibits and down-regulates P450 enzymes in vivo and in vitro, with a particular focus on the mechanisms by which these effects are achieved.

Keywords:

• Cytochrome P450
• nitric oxide
• inflammation
• protein degradation
• enzyme inhibition
• gene transcription

Disclosure statement

The authors declare no financial or other conflicts of interest with this work.

Additional information

Funding

This work was supported by the National Institutes of Health Institute of General Medical Science under Grant R01 GM 069971; the Slovenian Research Agency (ARRS) program under Grant P1-0390 and Project J1-9176; Kaja Blagotinsek Cokan was supported by a graduate fellowship of ARRS.