Induced expression of CYP2A5 in inflamed trematode-infested mouse liver

Montero, Regina; Gentile, Glenda J.; Frederick, Lori; McMannis, John D.; Murphy, Timothy F.; Silva, G.; Blankespoor, Harvey D.; Gentile, James M.

doi:10.1093/mutage/14.2.217

Cited by 35 publications

(30 citation statements)

References 27 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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“…Expression of CYP2A mRNAs and proteins is inducible by inflammation, microbial and parasitic infection, and cancer (Montero et al, 1999;Su and Ding, 2004). C. rodentium infection induced hepatic CYP2A5 mRNA to 180% of control in HeOu mice (Fig.…”

Section: Discussionmentioning

confidence: 98%

HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURINGCITROBACTER RODENTIUMINFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

Richardson¹,

Sherman²,

Antonovic³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Citrobacter rodentium is the rodent equivalent of human enteropathogenic Escherichia coli infection. This study investigated regulation of hepatic and renal cytochrome P450 (P450) mRNAs, hepatic P450 proteins, cytokines, and acute phase proteins during C. rodentium infection. Female C3H/HeOuJ (HeOu) and C3H/HeJ (HeJ) mice [which lack functional toll-like receptor 4 (TLR4)] were infected with C. rodentium by oral gavage and sacrificed 6 days later. Hepatic CYP4A10 and 4A14 mRNAs were decreased in HeOu mice (<4% of control). CYP3A11, 2C29, 4F14, and 4F15 mRNAs were reduced to 16 to 55% of control levels, whereas CYP2A5, 4F16, and 4F18 mRNAs were induced (180, 190, and 600% of control, respectively). The pattern of P450 regulation in HeJ mice was similar to that in HeOu mice for most P450s, with the exception of the TLR4 dependence of CYP4F15. Hepatic CYP2C, 3A, and 4A proteins in both groups were decreased, whereas CYP2E protein was not. Renal CYP4A10 and 4A14 mRNAs were significantly down-regulated in HeOu mice, whereas other P450s were unaffected. Most renal P450 mRNAs in infected HeJ mice were increased, notably CYP4A10, 4A14, 4F18, 2A5, and 3A13. Hepatic levels of interleukin (IL)-1␤, IL-6, and tumor necrosis factor ␣ (TNF␣) mRNAs were significantly increased in infected HeOu mice, whereas only TNF␣ mRNA was significantly increased in HeJ mice. Hepatic ␣ 1 -acid glycoprotein was induced in both groups, whereas ␣-fibrinogen and angiotensinogen were unchanged. These data indicate that hepatic inflammation induced by C. rodentium infection is mainly TLR4-independent and suggest that hepatic P450 down-regulation in this model may be cytokine-mediated.

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“…Furthermore, these conditions appear to be associated with increased serum bilirubin levels (Bonacini, 2004;Malaguarnera et al, 2005;Richardson et al, 2006b;Hansen, 2010). (Pellinen et al, 1993) Chloroform Anesthetic/Teflon (Camus et al, 1996) Cocaine Topical anesthetic (Pellinen et al, 1994a(Pellinen et al, , 1994b) Ethanol Fuel, beverage, and antiseptic (Lu et al, 2010) Phenobarbital Barbiturate and anticonvulsant (Hahnemann et al, 1992;Salonpää et al, 1994) Pyrazole Precursor for various medicines (Juvonen et al, 1985;Nichols and Kirby, 2008 (Cai et al, 2002) Buthionine sulfoximine Drug used in chemotherapy to reduce levels of glutathione (Gilmore et al, 2003) pregnenolone 16a-carbonitrile (PCN) Pregnane X receptor (PXR) agonist or antiglucocorticoid (Cai et al, 2002) Rifampicin Bactericidal antibiotics (Donato et al, 2000) Trans-4,5-dihydroxy-1,2-dithiane (DTTox) Intramolecular disulfide form of dithiothreitol; reducing agent (Gilmore and Kirby, 2004) (Montero et al, 1999) Bilirubin Bilirubin (BR) is the end product of heme catabolism, and heme is found in hemoglobin or other hemoproteins such as cytochromes, catalase, and a small pool of unbound free heme (Roy-Chowdhury et al, 2007). BR consists of a tetrapyrrole ( Figure D1).…”

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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Induced expression of CYP2A5 in inflamed trematode-infested mouse liver

Cited by 35 publications

References 27 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

HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURINGCITROBACTER RODENTIUMINFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE

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

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