Cytochrome P450 and Antioxidant Activity in Interleukin-6 Knockout Mice After Induction of the Acute-Phase Response

Abstract

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.

Hepatic Cytochrome P450s, Phase II Enzymes and Nuclear Receptors Are Downregulated in a Th2 Environment during Schistosoma mansoni Infection

“…We and others have attributed the changes in P450 expression in the LPS and C. rodentium models to the production of proinflammatory cytokines associated with the innate immune response [interleukin (IL)-1b, , and tumor necrosis factor-a (TNFa)] (Siewert et al, 2000;Warren et al, 2001;Aitken et al, 2006;Xu et al, 2006;Aitken and Morgan, 2007;Nyagode et al, 2010). There is some evidence that hepatic P450 downregulation during inflammation may be at least partly mediated by modulation of nuclear receptors including peroxisome proliferator-activated receptor-a (PPARa), pregnane X receptor (PXR), constitutive androstane receptor (CAR), retinoid X receptor-a (RXRa), and farnesoid X receptor (FXR) (Beigneux et al, 2002;Teng and Piquette-Miller, 2005;Kosters et al, 2009;Gerbal-Chaloin et al, 2013).…”

Suppression of Drug-Metabolizing Enzymes and Efflux Transporters in the Intestine of Endotoxin-Treated Rats

“…Expression of PGP, MRP2, and CYP3A are all reduced in animal livers during infection or inflammation (Morgan, 1997;Piquette-Miller et al, 1998;Tang et al, 2000;Payen et al, 2002). In vivo and in vitro studies indicate that interleukin-6 (IL-6) and other pro-inflammatory cytokines released during the inflammatory response are primarily involved in mediating this downregulation (Sukhai et al, 2000;Hartmann et al, 2001;Lee and Piquette-Miller, 2001;Warren et al, 2001). Although the molecular mechanism of this phenomenon has yet to be elucidated, it is possible that these proteins share common regulatory pathways.…”

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

“…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. Using "knockout" mice deficient in TNF␣ or IL-6 responses, we have shown that endogenous TNF␣ and IL-6 modulate constitutive as well as LPS-induced changes in hepatic P450 expression (Warren et al, 1999(Warren 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. Using "knockout" mice deficient in TNF␣ or IL-6 responses, we have shown that endogenous TNF␣ and IL-6 modulate constitutive as well as LPS-induced changes in hepatic P450 expression (Warren et al, 1999(Warren et al, , 2001. The mechanism by which cytokines affect P450 expression is presently unknown.…”