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.
ABSTRACT
The aim of this study was to evaluate small doses of known cytochrome P450 enzyme inhibitors, grapefruit juice (GFJ) and one of its components, bergamottin (BGT), for the prevention of paracetamol (PAR)-induced hepatotoxicity after overdose in rats. Six groups of 15 Sprague Dawley (SD) rats each were treated with single oral doses of either saline, PAR only 1725 mg/kg, PAR + GFJ low dose (2 ml) and PAR + GFJ high dose (3 ml), PAR + BGT 0.05 mg/kg (BGT-low) and PAR + BGT 0.22 mg/kg (BGT-high). Thereafter, 5 rats from each group were sacrificed after 24, 48 and 72 h and, on each occasion, blood samples were collected for determination of liver and renal function, full blood count (FBC) and PAR concentration. A piece of liver was sent for histopathology. By 48 h the liver enzymes in the PAR-only group were significantly (P < 0.05) higher than in the PAR + GFJ and PAR + BGT groups, i.e., alanine transaminase (ALT) 837 ± 268 u/L and aspertate transaminase (AST) 1359 ± 405 for PAR only; versus ALT 34 ± 48.8 u/L and AST 238 ± 221 for PAR + GFJ-high; ALT 22 ± 13.9 and AST168 ± 49.6 for PAR + BGT-high; and ALT 52 ± 7.2 u/L and AST 147 ± 153 for the control group. The results correlated with the histopathology findings where livers of the PAR-only group exhibited severe centrilobular and hepatocyte necrosis. In conclusion, GFJ and BGT prevented PAR-induced hepatotoxicity after PAR overdose in rats, and this calls for appropriate observation studies in humans.
ABSTRACT
In this study, the role of the immune system in nevirapine- (NVP-) induced subclinical liver injury was investigated by observing for changes of some immune parameters during the initial stages of NVP-induced hepatotoxicity in a rat model. In the acute phase, two test-groups of 10 Sprague-Dawley rats each were administered with bacterial lipopolysaccharide (LPS) or saline (S) intraperitoneally, followed by oral NVP, after which 5 rats from each group were sacrificed at 6 and 24 hours. For the chronic phase, two groups of 15 rats each received daily NVP, and on days 7, 14, and 21, five rats from each group were administered with either LPS or S, followed by that day's NVP dose, and were sacrificed 24 hours later. NVP caused liver injury up to seven days and progressively increased IL-2 and IFN-γ levels and lymphocyte count over the 21 days. NVP-induced liver injury was characterized by apoptosis and degeneration changes, while, for LPS, it was cell swelling, leukostasis, and portal inflammation. Coadministration of NVP and LPS attenuated NVP-induced liver injury. In conclusion, the immune system is involved in NVP toxicity, and the LPS effects may lay the clue to development of therapeutic strategies against NVP-induced hepatotoxicity.
