Inflammation and infection have long been known to downregulate the activity and expression of cytochrome P450 (CYP) enzymes involved in hepatic drug clearance. This can result in elevated plasma drug levels and increased adverse effects. Recent information on regulation of human CYP enzymes is presented, as are new developments in our understanding of the mechanisms of regulation. Experiments to study the effects of modulating CYP activities on the inflammatory response have yielded possible insights into the physiological consequences, if not the purpose, of the downregulation. Regulation of hepatic flavin monooxygenases, UDP-glucuronosyltransferases, sulfotransferases, glutathione S-transferases, as well as of hepatic transporters during the inflammatory response, exhibits similarities and differences with regulation of CYPs.

Hepatic P450 activities are profoundly affected by various infectious and inflammatory stimuli, and this has clinical and toxicological consequences. Whereas the expression of most P450s in the liver is suppressed, some are induced. Many of the effects observed in vivo can be mimicked by pro-inflammatory cytokines and IFNs, and P450s are differentially regulated by these agents. Therefore, different cytokine profiles and concentrations in the vicinity of the hepatocyte in different models of inflammation may result in qualitatively and quantitatively different effects on populations of P450s. In addition to cytokines, glucocorticoids may have an important role in P450 regulation in stress conditions, including that caused by inflammatory stimuli. Although in many cases the decreases in activity are due primarily to a down-regulation of P450 gene transcription, it is likely that modulation of RNA and protein turnover, as well as enzyme inhibition, contributes to some of the observed effects. The mechanisms whereby these effects are produced may also vary with both the P450 under study and the time course of the effect. The complexity of the P450 response to inflammation and infection means that all of the above factors must be considered when trying to predict the effect of a given infectious or inflammatory condition on the clinical or toxic response of humans or animals to an administered drug or toxin. The question of whether the down-regulation of the hepatic P450 system to inflammation or infection is a homeostatic or pathological response cannot be answered at present. It is difficult to discern the physiological benefit of reducing hepatic P450 activities, unless it is to prevent the generation of reactive oxygen species generated by uncoupled catalytic turnover of the enzymes. On the other hand, as we proposed some years ago [64], the suppression of P450 may be due to the liver's need to utilize its transcriptional machinery and energy for the synthesis of APPs involved in the inflammatory response. In that case, one could ask why the organism has gone to the trouble of employing differential mechanisms for suppression of P450. One answer could be that the response evolved after the divergence of many of the P450 genes, necessitating the evolution of multiple redundant mechanisms for P450 suppression. In contrast to the down-regulation of P450s in the liver, the induction of several forms in this and other tissues suggests a more specific homeostatic role of these effects, e.g., in generation or catabolism of bioactive metabolites.

Infection and inflammation are associated with down-regulations of hepatic and extrahepatic cytochrome P450s, as well as other drug metabolizing enzymes and transporters. We will review the genesis of inflammatory reactions, and discuss the relevance of the inflammatory regulation of P450 enzymes observations to clinical drug-disease and drug-drug interactions. Mechanistically, understanding the enzyme specificity and mechanisms of regulation will allow us to make better decisions about drug dosage regimens when a patient’s inflammatory status changes.

ABSTRACT:Cytochromes P450 (P450s) are down-regulated in hepatocytes in response to inflammation and infection. This effect has been extensively studied in animal models, but significantly less is known about responses in humans and even less about responses in the absence of inducing agents. This article focuses on the effects of bacterial lipopolysaccaride (LPS), interleukin-6 (IL-6), tumor necrosis factor-␣ (TNF), interferon ␥ (IFN), transforming growth factor-␤ (TGF) and interleukin-1␤ (IL-1) on expression of CYP2B6 and the CYP2C mRNAs in human hepatocytes. These effects were compared with responses of the better studied and more abundant CYP3A4. CYP3A4 and CYP2C8 were down-regulated by all cytokine treatments. CYP2C18, which is expressed at very low levels in liver, was unaffected by cytokine treatments. The other CYP2Cs and CYP2B6 showed cytokine-specific effects. CYP2C9 and CYP2C19 showed almost identical response patterns, being downregulated by IL-6 and TGF but not significantly affected by LPS, TNF, IFN, or IL-1. CYP2B6 mRNA responded only to IL-6 and IFN. IL-6 down-regulated the mRNAs of all P450s studied. Western blot analysis of P450 protein expression supported the mRNA data to a large extent, although some inconsistencies were observed. Our results show that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 responses to inflammation are independently regulated and indicate that this fine control may have a critical effect on human drug responses in disease states.The liver responds to inflammation and infection by increasing levels of acute-phase proteins and concurrently down-regulates liverspecific proteins involved in drug metabolism (Morgan, 1997;Renton, 2004;Aitken et al., 2006). Cytochromes P450 (P450s) are the major drug-metabolizing enzymes in the liver and are significantly down-regulated by infection and inflammatory stimuli (Morgan, 1997;Aitken et al., 2006). The rapid down-regulation of P450 mRNAs (Morgan, 1997) has led to a focus on transcription as the primary mechanism of these effects, and this view is supported by the size and speed of transcriptional down-regulation as demonstrated in rats in vivo (Cheng et al., 2003). In humans, this down-regulation is associated with decreased drug clearance (Kraemer et al., 1982;Rivory et al., 2002;Carcillo et al., 2003;Renton, 2004) and can result in increased incidence of drug toxicity (Kraemer et al., 1982).Three lines of evidence support a major role of inflammatory cytokines as the mediators of P450 regulation in the liver during inflammation. First, cytokines can down-regulate P450 expression in cultures of rodent and human hepatocytes (Abdel-Razzak et al., 1993;Morgan, 1997;Sunman et al., 2004;Aitken et al., 2006). Second, mice with null mutations in cytokine or cytokine receptor genes display diminished P450 down-regulation in response to some inflammatory stimuli (Siewert et al., 2000;Ashino et al., 2004). Third, P450-dependent drug clearance has been correlated inversely with plasma interleukin-6 (IL-6) in patients with tumors (Rivory et al...

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