ABSTRACT:This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 07 meeting in Washington, DC. The presentations discussed the phenomenology, clinical consequences, and underlying mechanisms of cytochrome P450 and drug transporter regulation by inflammatory and infectious stimuli. Although considerable insights into the links between inflammatory mediators and altered hepatic drug clearance pathways have been gained from previous studies with acute inflammatory stimuli, this symposium highlighted recent advances in understanding how these processes operate in other organs and chronic inflammatory states relevant to human diseases. The development of mouse models of live bacterial infection provides excellent opportunities to explore the impact of infection on drug metabolism beyond the well characterized effects of bacterial endotoxin. Altered levels of cytochromes P450 and especially drug transporters due to inflammation in brain, intestine, and placenta have significant implications for the use of many drugs in diverse clinical settings. The consequences of inflammatory cytokine production by tumors for drug safety and efficacy in cancer patients were outlined. Repression of drug clearance pathways by tumor-derived cytokines may result in extreme toxicity to chemotherapy, compromising treatment of many cancers. It is fitting that, in honoring the career contributions and achievements of Dr. Kenneth W. Renton, this symposium reinforced the clinical relevance of this field.Inflammation regulates the expression, activity, and functions of many drug-metabolizing enzymes and drug transporters. Although impairment of drug-metabolizing enzyme activities during inflammation has been known to occur for half a century, regulation of transporters by inflammation was recognized relatively recently, in the last decade. Although the regulation of both cytochrome P450s (P450s) and drug transporters has profound implications for clinical drug therapy in disease states, research on inflammation in drug metabolism and transporters has tended to proceed in parallel. This symposium was organized to bring the areas together to identify commonalities and differences in the regulation of transporters and drug-metabolizing enzymes and to promote cross-fertilization of knowledge. It is appropriate then, that this symposium also recognized the career and contributions of Dr. Kenneth W. Renton on the occasion of his retirement.The diverse presentations on regulation of both P450 enzymes and drug transporters revealed that the regulation of both systems in inflammation, infection, and cancer have much in common. In the face of a global inflammatory stimulus such as bacterial endotoxin
The expression of cytochrome P450 and related biotransformation is altered during the operation of host defense mechanisms. This has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs is severely compromised. In most cases individual cytochrome P450 forms are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA, protein and enzyme activity. The loss in drug metabolism is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors. Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation. When inflammatory responses are confined to the brain there is a loss of cytochrome P450 not only in the brain but also in peripheral tissues. This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source. In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component. This often results in altered drug responses and increased toxicities. Inflammation mediated alterations in the metabolism of endogenous compounds can lead to altered physiology. Changes in drug handling capacity during inflammation/infection will continue to be one of the many factors that complicate therapeutics.
The expression and activity of cytochrome P450 (CYP) is altered during periods of infectious disease or when an inflammatory response is activated. Most of the major forms of CYP are affected in this manner and this leads to a decrease in the capacity of the liver and other organs to handle drugs, chemicals and some endogenous compounds. The loss in drug metabolism is predominantly an effect resulting from the production of cytokines and the modulation of the transcription factors that control the expression of specific CYP forms. In clinical medicine numerous examples have been reported indicating the occurrence of compromised drug clearance and changes to pharmacokinetics during disease states with an inflammatory component or during infections. For any drug that is metabolised by CYP and has a narrow therapeutic index, there is a significant risk in placing patients in a position where an infection or inflammatory response might lead to aberrant drug handling and an adverse drug response.
1 Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P-glycoprotein (P-gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P-gp expression and function in the brain and liver. 2 Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When 3 H-digoxin was used at discrete time points, as a probe for P-gp function in vivo, an increase in brain and liver 3 H-radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a +/+ mice but not in mdr1a À/À mice 24 h after administering LPS i.c.v. 3 In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P-gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment. 4 Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P-gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P-gp function in that organ.
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