Role of biotransformation in 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione-induced hepatotoxicity in Fischer 344 rats

Abstract

Cytochrome P450 (CYP)-mediated metabolism in the thiazolidinedione (TZD) ring may contribute to the hepatotoxicity of the insulin-sensitizing agents such as troglitazone. We were interested in determining if biotransformation could also be a factor in the liver damage associated with another TZD ring containing compound, 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT). Therefore, hepatotoxic doses of DCPT (0.6 or 1.0 mmol/kg, i.p.) were administered to male Fischer 344 rats after pretreatment with vehicle, 1-aminobenzotriazole (ABT, non-selective CYP inhibitor) and troleandomycin (TAO, CYP3A inhibitor). Alternatively, rats were pretreated with vehicle or the CYP3A inducer dexamethasone (DEX) prior to a non-toxic DCPT dose (0.2 mmol/kg, i.p.). Vehicle-, ABT-, TAO-and DEX-only control groups were also run. Toxicity was assessed 24 hours after DCPT administration. Both hepatotoxic doses of DCPT induced elevations in serum alanine aminotransferase (ALT) levels that were attenuated by ABT or TAO pretreatment. Liver sections from rats that received vehicle + DCPT revealed areas of gross necrosis and neutrophil invasion, whereas sections from ABT + DCPT and TAO + DCPT rats showed minor changes compared to controls. DEX pretreatment potentiated ALT levels associated with the non-toxic DCPT dose. Furthermore, DEX + DCPT rat liver sections exhibited hepatic injury when compared against rats that received vehicle + DCPT. Blood urea nitrogen levels, urinalysis and kidney morphology were not markedly altered by any combination of pretreatments or treatments. Enzyme activity and Western blotting experiments with rat liver microsomes confirmed the effects of the various pretreatments. Our results suggest that hepatic CYP3A isozymes may be involved in DCPT-induced liver damage in male rats. We believe this is the first report demonstrating that modulation of the biotransformation of a TZD ring-containing compound can alter hepatotoxicity in a common animal model.

Carbamazepine-Induced Liver Injury Requires CYP3A-Mediated Metabolism and Glutathione Depletion in Rats

“…Although TAO is known as a potent and specific CYP3A inhibitor (Kostrubsky et al, 1997;Crincoli et al, 2008), KTZ has been reported to inhibit potently not only CYP3A1/2 activities but also CYP2C11 activity by a study using vaculovirus-infected insect cells expressing each rat P450 (Kobayashi et al, 2003). To examine whether KTZ treatment affected hepatic CYP3A and CYP2C enzyme activities in the rats, MDZ and TOL hydroxylase activities were measured in the microsomes prepared from livers collected 1.5 hours after the KTZ administration in rats administered CBZ at a dose of 400 mg/kg once daily for 4 days.…”

A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma

“…Blood smears did not demonstrate morphologic abnormalities in any cell lineage. Because this chemotype has been associated with hepatotoxicity, 37 blood chemistry analyses including alanine transferase, albumin, total protein, alkaline phosphatase, amylase, and total bilirubin, were undertaken at the time of killing, but did not disclose any abnormalities. Renal and pancreatic function was also normal.…”

Cytotoxicity of 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT) and analogues in wild type and CYP3A4 stably transfected HepG2 cells

“…Because DCPT contains a TZD ring and produces hepatotoxicity in a common laboratory animal, it may be useful for investigating TZD ring-induced liver damage. Further investigations showed that the toxicity of DCPT in male rats is dependent on CYP3A-mediated biotransformation (Crincoli et al, 2008). Pre-treating rats with dexamethasone, a CYP3A inducer, exacerbated liver damage of an otherwise non-toxic dose of DCPT.…”