Abstract
Inflammation and infection downregulate the activity and expression of cytochrome P450s (P450s) and other drug metabolizing enzymes (DMEs) involved in hepatic drug clearance. Schistosoma mansoni infection was reported to cause a downregulation of hepatic P450-dependent activities in mouse liver, but little is known about the specific enzymes affected or whether phase II DMEs are also affected. Here we describe the effect of murine schistosomiasis on the expression of hepatic P450s, NADPH-cytochrome P450 reductase (Cpr), phase II drug metabolizing enzymes, and nuclear receptors at 30 and 45 days postinfection (dpi). Although the hepatic expression of some of these genes was altered at 30 dpi, we observed substantial changes in the expression of the majority of P450 mRNAs and proteins measured, Cpr protein, as well as many of the UDP-glucuronosyltransferases and sulfotransferases at 45 dpi. S. mansoni infection also altered nuclear receptor expression, inducing mRNA levels at 30 dpi and depressing levels at 45 dpi. S. mansoni evoked a T helper 2 (Th2) inflammatory response at 45 dpi, as indicated by the induction of hepatic Th2 cytokine mRNAs [interleukins 4, 5, and 13], whereas the hepatic proinflammatory response was relatively weak. Thus, chronic schistosomiasis markedly and selectively alters the expression of multiple DMEs, which may be associated with Th2 cytokine release. This would represent a novel mechanism of DME regulation in disease states. These findings have important implications for drug testing in infected mice, whereas the relevance to humans with schistosomiasis needs to be determined.
Footnotes
- Received September 17, 2013.
- Accepted October 25, 2013.
S.M.M. and B.A.N. contributed equally to this work.
This research was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072372 (to E.T.M.)] and the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R01-AI101982 (to R.D.C.)].
A portion of this work was previously presented: Nyagode BA, Prasanphanich N and Morgan ET (2012) Changes in the expression of murine xenobiotic metabolizing enzyme mRNAs after Schistosoma mansoni infection. 2012 North American Meeting of the International Society for the Study of Xenobiotics; 2012 Oct 14–18; Dallas, TX.
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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