Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

De-Oliveira, A.C.A.X.; Carvalho, Renato S.; Paixao, F.; Tavares, Hellen S; Gueiros, Luciana S.; Siqueira, Carolina M; Paumgartten, Francisco José Roma

doi:10.1186/1475-2875-9-81

Cited by 19 publications

(30 citation statements)

References 55 publications

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“…In contrast to many P450s that are downregulated during infections, Cyp2a5 was induced in malarial, helminthic, viral, and bacterial infections as well as by hepatotoxic compounds (Kirby et al, 1994;Sipowicz et al, 1997;Montero et al, 1999;De-Oliveira et al, 2010;Abu-Bakar et al, 2013). On the contrary, our results showed a downregulation of Cyp2a4/5 at both mRNA and protein levels, a trend that was also observed during bacterial infection with C. rodentium (Chaluvadi et al, 2009).…”

Section: Discussioncontrasting

confidence: 49%

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: Discussioncontrasting

confidence: 49%

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 mechanism of the unique regulation of Cyp2a5 during these conditions is unclear and remains to be investigated. The one demonstrated mechanism that is common in these conditions is, in part, oxidative stress (Kirby et al, 1994b;Chomarat et al, 1997;Nebert et al, 2000;Cheung et al, 2003;Gilmore et al, 2003;Gilmore and Kirby, 2004;Su and Ding, 2004;Weng et al, 2005;Chen and Siddiqui, 2007;Fisher et al, 2009;De-Oliveira et al, 2010). Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010).…”

Section: Pathophysiological States Associated With Cyp2a5mentioning

confidence: 99%

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Kim

Antenos

Squires

et al. 2013

Toxicology and Applied Pharmacology

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Murine cytochrome P450 2A5 (CYP2A5) is an interesting enzyme for its unique regulation and its involvement in liver injury caused by various well-known pathological conditions or hepatotoxins. It has been reported that CYP2A5 is upregulated following exposure to chemical hepatotoxins and during pathophysiological conditions in which the levels of most Cytochrome P450s are either unchanged or down-regulated. Recently bilirubin has been identified as the first endogenous substrate for CYP2A5 and it has been suggested that CYP2A5 plays a major role in bilirubin clearance as an alternative mechanism to BR conjugation by UGT1A1. This study investigated the mechanisms of gene regulation and cytoprotective role of CYP2A5 in response to bilirubin treatment in liver. Our results demonstrate that bilirubin induces CYP2A5 expression at the mRNA and protein levels by increasing CYP2A5 transcription via a mechanism that involves Nrf2 activation. Furthermore, our results suggest that induced CYP2A5 plays a cytoprotective role against bilirubin toxicity by directly lowering the cellular levels of bilirubin and by inhibiting caspase-3 activation.iii ACKNOWLEDGEMENTS

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“…In animal models, cytochrome P450 is depressed by various types of: (i) bacterial infections -Listeria monocytogenes (12), Actinobacillus pleuropneumoniae (13), Chlamydia trachomatis (14), (ii) viral infection -Encephalomyocarditis virus (15), murine retrovirus LP-BM5 (16), in uenza virus (17), (iii) parasitic infections -Fasciola hepatica (18), Plasmodium berghei (19), and (iv) Bacillus Calmette-Guerin (BCG) (20) and B. pertussis (21) vaccines.…”

Section: Experimental Evidencesmentioning

confidence: 99%

Immune system - drug metabolism interactions: Toxicological insight

Yanev

2014

Adipobiology

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From many years the in ammation is considered as one important determinant of susceptibility to intoxication by xenobiotic exposure. In ammation and vaccination in most cases are connected with immune system stimulation and release of cytokines, adipokines, reactive oxygen species, nitric oxide, proteases, and lipid metabolites. That was accompanied by di erent extend of down-regulation of the main xenobiotic/drug metabolizing enzyme system cytochrome P450 (CYP) both in the liver and the adipose tissue. We need more knowledge of possible changes in the pharmacokinetics respectively in e ectiveness and side e ects of drugs used in chronically ill patients in case of occurrence of acute viral or bacterial infection in them or after the application of di erent vaccines. This would contribute signi cantly to the optimization of personal drug therapy avoiding toxicity or lack of e ectiveness. Here we tried to summarize some of the main experimental and clinical data of altered drug metabolizing enzyme system in the case of changes in the immune system due to in ammation or vaccination. 2014; 6: 31-36 Adipobiology

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Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

Cited by 19 publications

References 55 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

Cytochrome P450 2A5 and bilirubin: Mechanisms of gene regulation and cytoprotection

Immune system - drug metabolism interactions: Toxicological insight

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