Changes in IL-2 and IL-10 during Chronic Administration of Isoniazid, Nevirapine, and Paracetamol in Rats.

Zanelle Bekker,Andrew Walubo,Jan B Du Plessis

doi:10.1155/2016/3094783

Zanelle Bekker, Andrew Walubo + Show 1 more

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https://doi.org/10.1155/2016/3094783

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Abstract

The aim of this study was to illustrate the initial subclinical drug-induced liver injury and the associated adaptive immune response by monitoring for the changes in plasma IL-2, IL-10, and some cytochrome P450 activity during chronic administration of nevirapine (NVP), isoniazid (INH), and paracetamol (PAR) in rats without clinical hepatotoxicity. Male Sprague-Dawley (SD) rats were divided into four groups (saline (S), NVP, INH, and PAR) of 25 animals each. The drugs were administered daily for 42 days at therapeutic doses (NVP 200 mg/kg, PAR 500 mg/kg, and INH 20 mg/kg) to the respective groups by oral gavage and five rats per group were sacrificed weekly. All the three drugs induced a subclinical liver injury in the first 2-3 weeks followed by healing, indicating adaption. The liver injury was pathologically similar and was associated with immune stimulation and increased cytochrome P450 activity. NVP- and PAR-induced liver injury lasted up to 14 days while that for INH lasted for 28 days. NVP-induced liver injury was associated with increased IL-2, CD4 count, and CYP3A2 activity, followed by increased IL-10 during the healing phase. In conclusion, the initial drug-induced subclinical liver injury, its spontaneous healing, and the associated adaptive immune response have been demonstrated.

Highlights

Drug-induced liver injury is a major contributor to adverse drug reactions that has restricted the use of efficacious drugs such as isoniazid (INH) and nevirapine (NVP), while paracetamol (PAR) overdose is associated with fatal drug-induced liver injury
The elimination process is mediated by proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-2, and IL-4, while the counter mechanisms are mediated by anti-inflammatory cytokines such as IL-6, IL10, and IL-13
This study has demonstrated the initial subclinical druginduced liver injury and its subsequent healing in association

Summary

Introduction

Drug-induced liver injury is a major contributor to adverse drug reactions that has restricted the use of efficacious drugs such as isoniazid (INH) and nevirapine (NVP), while paracetamol (PAR) overdose is associated with fatal drug-induced liver injury. Several mechanisms regarding INH, NVP, and PAR-induced hepatotoxicity have been postulated, the immune system has been implicated as a mediator and major determinant for progression of the liver injury [1,2,3,4]. The immune system is activated and starts a process to eliminate hepatocytes expressing these immunogenic adducts [10,11,12,13]. It was explained that most patients do not develop hepatotoxicity because their counter mechanisms are able to efficiently eliminate the antigenic adducts and/or to counter the proinflammatory response [14,15,16,17]. In a few individuals, there is failure to counter the proinflammatory response, and this leads to progressive destruction of hepatocytes and overt druginduced hepatotoxicity ensues [16, 17]. Several reports have described increased levels of some proinflammatory cytokines during hepatotoxicity by INH [18], PAR [19], and NVP [20]

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