Endotoxin depresses hepatic cytochrome P450‐mediated drug metabolism in women

Abstract

Aims In men, the inflammatory response to intravenous endotoxin depresses apparent oral clearances of antipyrine, hexobarbitone, and theophylline. The aim of this study was to investigate whether there might be gender differences in the regulation of hepatic cytochromes P450. Methods Experiments were carried out in seven healthy women volunteers (ages 19-51, median 22 years). Each woman received a cocktail of the three drugs on two occassions, once after a saline injection and again after endotoxin. Results Endotoxin injections, but not saline, caused the expected physiologic responses of inflammation including fever and increases in circulating tumor necrosis factor-a, interleukin-6, and C-reactive protein. When compared with the saline control studies, endotoxin significantly decreased clearances of all probes: antipyrine, 31% (95%CI 21%-41%); hexobarbitone, 20% (95%CI 10-31%); and theophylline, 20% (95%CI 10%-30%). The decreases were comparable with those found in the men previously studied (35%, 27%, and 22%, respectively). Conclusions These data show that endotoxin-induced inflammation decreases hepatic cytochrome P450-mediated metabolism of selected probe drugs in women as it does in men.Keywords: antipyrine, cytochrome P450, drug metabolism, endotoxin, gender, hexobarbitone, inflammation, theophylline Gender differences in the metabolism of a number of Introduction drugs have been reported [(18-21)]. Differences for the most part were small, most medications appeared to be TGram-negative bacterial sepsis is still a leading cause of death in the intensive care setting [1, 2] and both men and metabolized similarly in men and women, and a recent report [22] saw no gender differences in amounts of specific women are susceptible to the sequelae of sepsis. A preliminary study [3] of drugs given to these patients P450 proteins in samples of normal liver. However, whether there are important gender differences in the way inflamrevealed that a mean (±s.d.) of 12.1±3.9 systemically active xenobiotic drugs are administered during the period mation affects regulation of P450s has not yet been investigated. To address this question, the current study of sepsis. Animal models of sepsis using endotoxin (lipopolysaccharide or LPS) to elicit the inflammatory response [4][5][6][7][8] administered AP, HB, and TH drug probe cocktails to female volunteers and assessed the effects of two consecutive and administration of inflammatory cytokines such as interleukin-1, tumor necrosis factor, and interleukin-6 [7, LPS injections on expression of the acute phase response and on clearances of the drug probes. 9-14] have demonstrated significant decreases in hepatic cytochrome P450-mediated drug metabolism. Therefore, it is likely that septic patients who have high levels of Methods inflammatory cytokine production have depressed hepatic Nine female volunteers aged 21-51 years participated in P450 activities which could be clinically significant. Our this study. Two were excluded as explained below. The group recently addressed the ...

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…This effect evolved over a 24 hour period and its intensity correlated with the intensity of the inflammatory response, although there was no statistically significant correlation between the observed effects and levels of any of the cytokines. A later study by the same investigators confirmed a similar effect in vivo in female volunteers (Shedlofsky et al, 1997). However, an inverse correlation has been reported between plasma IL-6 levels and cytochrome P450-dependent drug clearance of erythromycin (measured by breath test) by CYP3A4 in patients with advanced cancer (Rivory et al, 2002) and of caffeine and mephenytoin by CYP1A2 and CYP2C19, respectively, in patients with congestive heart failure (Frye et al, 2002).…”

“…IL-1, IL-6, and TNF-a are believed to be the principal proinflammatory cytokines that induce changes in liver protein expression; typically, they downregulate their expression. The precise mechanisms are not fully understood but these cytokines bind to their corresponding receptors on the cell surface in target organs and activate intracellular signaling systems that regulate gene transcription and biosynthesis of a whole range of enzymes and transporters, including those involved in drug metabolism and disposition (Shedlofsky et al, 1994(Shedlofsky et al, , 1997Morgan, 1997;Morgan et al, 1998;Renton, 2004Renton, , 2005Aitken et al, 2006;Le Vee et al, 2008, 2009Fardel and Le Vée, 2009). …”

Regulation of Cytochrome P450 4F11 by Nuclear Transcription Factor-κB

“…This defense mechanism and the release of these cytokines usually result in the down-regulation of many isoforms of cytochrome P450 (P450) (Ghezzi et al, 1986;Shedlofsky et al, 1987Shedlofsky et al, , 1997Bertini et al, 1988;Morgan 1989;Wright and Morgan 1990). This is important because of the major roles of the P450 systems in the metabolism of drugs used in the treatment of inflammatory conditions, as well as steroids, lipid-soluble vitamins, prostaglandins, and leukotrienes.…”

“…TNF-␣, one of the cytokines prominent in the inflammatory response, is known to be released during many types of infections and inflammatory diseases (Shedlofsky et al, 1997). In the current study, we used this cytokine to define the effects of its presence on the regulation of CYP4F11, an isoform of the 4F family whose substrate profile includes not only endogenous compounds but also xenobiotics, specifically pharmaceuticals (Kalsotra et al, 2004).…”

Enhanced Induction of Cytochrome P450 Enzymes and CAR Binding in TNF (p55−/−/p75−/−) Double Receptor Knockout Mice Following Phenobarbital Treatment

“…Inflammation has been observed clinically to reduce P450-related hepatic drug metabolism (Renton et al, 1980;Sonne et al, 1985). In human and animal experimental systems, we and others have demonstrated a significant decrease in hepatic P450 activity following induction of the acute phase response (APR) by the administration of bacterial endotoxin (LPS) (Shedlofsky et al, 1994(Shedlofsky et al, , 1997Sewer et al, 1996;Roe et al, 1998;Warren et al, 1999Warren et al, , 2001. Elevated levels of cytokines [e.g., tumor necrosis factor-alpha (TNF␣), interleukin-6 (IL-6), and interleukin-1␤ (IL-1␤)] have been implicated as the primary mediators of the APR and the accompanying decline in hepatic P450 expression (Heinrich et al, 1990;Schindler et al, 1990;van Deventer et al, 1990;Parmentier et al, 1993Parmentier et al, , 1997Warren et al, 1999Warren et al, , 2001.…”