Modulation of Cytochrome P450 2A5 Activity by Lipopolysaccharide: Low-Dose Effects and Non-Monotonic Dose-Response Relationship

Ana C A X De-Oliveira,Kátia S Poça,Paulo R R Totino,Francisco J R Paumgartten,Bernhard Ryffel

doi:10.1371/journal.pone.0117842

Ana C A X De-Oliveira, Kátia S Poça + Show 3 more

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https://doi.org/10.1371/journal.pone.0117842

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Journal: PLOS ONE	Publication Date: Jan 30, 2015
Citations: 8	License type: CC BY 4.0

Affiliation: Fundação Oswaldo Cruz

Abstract

Mouse cytochrome P450 (CYP) 2A5 is induced by inflammatory conditions and infectious diseases that down-regulate the expression and activity of most other CYP isoforms. Enhanced oxidative stress and nuclear factor (erythroid 2-related factor) 2 (Nrf2) transcription factor activation have been hypothesised to mediate up-regulation of CYP2A5 expression in the murine liver. The unique and complex regulation of CYP2A5, however, is far from being thoroughly elucidated. Sepsis and high doses of bacterial lipopolysaccharide (LPS) elicit oxidative stress in the liver, but depression, not induction, of CYP2A5 has been observed in studies of mice treated with LPS. The foregoing facts prompted us to evaluate the response of CYP2A5 liver activity in female DBA-2 mice over a broad range of LPS doses (0, 0.025, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, and 20 mg/kg). Cytokine levels (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17A, interferon gamma, tumour necrosis factor alpha) and nitric oxide (NO) were measured in the blood serum. Activities of CYP1A (EROD) and CYP2B (BROD) in the liver were also determined for comparative purposes. LPS depressed CYP2A5 at low doses (0.025–2.0 mg/kg) but not at doses (>2 mg/kg) that increased pro-inflammatory cytokines and NO serum levels, and depressed CYP1A and CYP2B activities. Blockade of pro-inflammatory cytokines and the overproduction of NO induced by co-treatment with pentoxifylline and LPS and iNOS inhibition with aminoguanidine both extended down-regulation of CYP2A5 to the high dose range while not affecting LPS-induced depression of CYP1A and CYP2B. Overall, the results suggested that NO plays a role in the reversal of the low-dose LPS-induced depression of CYP2A5 observed when mice were challenged with higher doses of LPS.

Highlights

Cytochrome P450 2A5 (CYP2A5) is a murine enzyme expressed in the liver and olfactory epithelium of the nasal cavity and to a lesser degree in other extra-hepatic tissues such as intestines, oesophagus, lung, and kidneys [1]
CYP2A5 is down-regulated by LPS doses that do not alter CYP1A and CYP2B activities and are insufficient to elicit any increase in pro-inflammatory cytokines and nitric oxide (NO) blood levels
When overproduction of pro-inflammatory cytokines and NO was blocked by PTX treatment, the activities of CYP1A, CYP2B, and CYP2A5 were all down-regulated by high doses of LPS

Summary

Introduction

Cytochrome P450 2A5 (CYP2A5) is a murine enzyme expressed in the liver and olfactory epithelium of the nasal cavity and to a lesser degree in other extra-hepatic tissues such as intestines, oesophagus, lung, and kidneys [1]. It is an orthologue of rat CYP2A3 and human CYP2A6/13 [1,2]. Oxidation of coumarin to 7-hydroxycoumarin is catalysed predominantly by CYP2A5, and the coumarin 7-hydroxylase (COH) reaction is considered a selective marker of its activity [3]. Many researchers believe that oxidation mediated by CYP2A5 in mice (or CYP2A6 in humans) contributes to the strict regulation of BR levels in liver tissue to achieve adequate balance between BR antioxidant (low concentrations) and cytotoxic effects (higher levels) [5,6,8,9]

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