Alterations of hepatic microsomal enzymes in the early phase of murine schistosomiasis

Manhães-Rocha, D.A.; Conte, Fernando de Paiva; Fidalgo-Neto, Antônio Augusto; De-Oliveira, A.C.A.X.; Pinto, Luís Felipe Ribeiro; Paumgartten, Francisco José Roma

doi:10.1016/j.actatropica.2005.04.013

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…Correspondingly, the apparent induction of some DME mRNAs at 30 dpi could be due to the downregulation of GAPDH. Nevertheless, the induction of some mRNAs at 30 dpi is consistent with previous reports of increases in some P450-dependent activities before eggs are laid (El-Bassiouni et al, 1984;Manhães-Rocha et al, 2005). Induction of Cyp4f18 and Cyp4f16 mRNAs at 45 dpi is not surprising considering the roles of Cyp4f enzymes in eicosanoid metabolism (Kalsotra and Strobel, 2006).…”

Section: Discussionsupporting

confidence: 80%

“…The activity of glutathione-S-transferase in the hepatic S9 fraction of Balb/C mice was increased at 33 dpi in animals infected with 60-180 cercariae and decreased in those exposed to 300-600 cercariae (Sheweita et al, 1998). No alterations of UGT activities were found during the early phase of schistosomiasis (Manhães-Rocha et al, 2005). Here we showed a significant depression of Ugt1a1, Ugt1a9, and Ugt2b5 mRNAs (67%-80%), and the same for Sult1b1, Sult1d1, and Sult2a1/2 (50%-87%).…”

Section: Discussionmentioning

confidence: 77%

“…The idea that Th2 cytokines are important for P450 regulation in this model is supported by studies in athymic nude mice and mice infected with unisexual S. mansoni parasites, showing that the downregulation of P450-associated activities during murine schistosomiasis is dependent on the presence of a robust adaptive immune response to parasite eggs (Cha et al, 1980a,b). Moreover, as shown here and by others studying P450-dependent enzyme activities, the dramatic effects of infection are only observed in the later phase when the immune reaction to parasite eggs and the granulomas around the eggs are maximal (Sheweita et al, 2002;Manhães-Rocha et al, 2005;Conte et al, 2007;Gotardo et al, 2011).…”

Section: Discussionmentioning

confidence: 79%

“…Much knowledge about the effects of schistosomiasis on P450-dependent drug metabolism has been gathered from studies on microsomal activities (Cha and Edwards, 1976;Cha et al, 1980a,b;Sheweita et al, 1998Sheweita et al, , 2002Manhães-Rocha et al, 2005;Conte et al, 2007;Gotardo et al, 2011). However, the contributions of mouse P450s to the metabolism of most drugs have not been rigorously established, and it is critical to know what happens to P450 gene products in this model.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…The eŠect of DBDE on the mutagenesis of MeIQx and BaP was observed regardless of sex, while diŠerences in the eŠect on the mutagenesis of NDMA were observed based on sex. Manh ãaes-Rocha et al reported that Schistosoma infection modulated the expression of CYPs in mice in a strain-and gender-speciˆc manner (28). Since the only CYP enzymes examined were MROD and EROD, the activities of which did not diŠer between males and females, the aforementioned gender-speciˆc diŠerence observed may be caused by an alteration of enzymes other than those examined in this study.…”

Section: Discussionmentioning

confidence: 47%

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

Fang

Nunoshiba²,

Yoshida³

et al. 2014

Genes and Environment

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It remains uncertain why non-genotoxic compounds that result in liver hypertrophy cause liver tumors. In an eŠort to resolve this issue, we examined whether liver postmitochondrial fraction (S9) prepared from rats treated with non-genotoxic compounds aŠected the genotoxicity of pro-mutagens. Known hepatotoxic compounds, such as piperonyl butoxide (PBO), decabromodiphenyl ether (DBDE), beta-naphtho‰avone (BNF), indole-3-carbinol (I3C) and acetaminophen (AA), were orally administered to male and female F344 rats at doses su‹cient to cause liver hypertrophy. Rats received diets containing each test compound for 3 days, 4 weeks or 13 weeks, and were then kept for 4 weeks without the test chemical. S9 prepared from the livers of each group was used for the Ames test with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (BaP) and N-nitrosodimethylamine (NDMA). In both sexes, liver hypertrophy was observed following administration of all test compounds, and was then reversed to the control state when administration ceased. The mutagenicity of MeIQx, BaP and NDMA increased with the use of S9 derived from rats treated with non-genotoxic compounds other than AA. DBDE administration had a marked eŠect on the mutagenicity of BaP (over a 30-fold increase in females) and NDMA (about a 20-fold increase in males). To estimate the involvement of metabolic enzymes in the alteration of mutagenicity, we measured the activity of ethoxyresoruˆn-O-deethylase (EROD) and methoxyresoruˆn-O-demethylase (MROD) (phase I enzymes), and UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) (phase II enzymes) in each S9 sample. The activity of phase I enzymes increased, even at the 3rd day following administration, and then decreased gradually, except in the case of AA, while the activity of phase II enzymes increased slightly. These results suggest that non-genotoxic hepato-hypertrophic compounds may be partly involved in carcinogenesis by modulating the metabolism of pre-carcinogens incorporated from the environment, in a manner that is dependent on sex and pre-incorporated chemicals.

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Regulation of Drug Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

Morgan

Lee

Nyagode

2012

Encyclopedia of Drug Metabolism and Interactions

146

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Under conditions of innate immune system activation (i.e., inflammation), the functions of specific cytochrome P450 enzymes, other drug metabolizing enzymes (DMEs), and drug transporters (DTs) are altered in the liver, small intestine, lung, kidney, and central nervous system (CNS). Many of these effects are primarily manifest at the transcriptional/RNA level, leading to corresponding changes in protein levels and function. This not only leads to altered drug and xenobiotic toxicity and action in diseased humans, but also has importance for disease therapy with biologic drugs that target inflammatory mediators or their receptors. Major roles for proinflammatory cytokines such as interleukin‐6 (IL‐6), IL‐1β, and tumor necrosis factor‐α(TNFα) are inferred from the abilities of these agents to affect DMEs and DTs in cultured cells and in vivo , but the in vivo contributions of cytokines to regulation of these proteins in different inflammatory disease states is still poorly understood.

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Alterations of hepatic microsomal enzymes in the early phase of murine schistosomiasis

Cited by 15 publications

References 23 publications

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

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

Effects of Oral Administration of Non-genotoxic Hepato-hypertrophic Compounds on Metabolic Potency of Rat Liver

Regulation of Drug Metabolizing Enzymes and Transporters in Infection, Inflammation, and Cancer

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