Effect of gender, dose, and time on 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT)-induced hepatotoxicity in Fischer 344 rats

Abstract

1. The thiazolidinedione (TZD) ring present in drugs available for type II diabetes may contribute to hepatic injury. Another TZD ring-containing compound, 3-(3,5dichlorophenyl)-2,4-thiazolidinedione (DCPT), produces liver damage in rats. Accordingly, the effects of gender, dose and time on DCPT hepatotoxicity were therefore evaluated. 2. Male rats were more sensitive to DCPT (0.4-1.0 mmol/kg by i.p. administration) as shown by increased serum alanine aminotransferase (ALT) levels and altered hepatic morphology 24 h post-dosing. Effects in both genders were dose-dependent. In males, DCPT (0.6 mmol/kg) produced elevations in ALTs and changes in liver sections 3 h after dosing that progressively worsened up to 12 h. DCPT-induced renal effects were mild. 3. We conclude that male rats are more susceptible to DCPT hepatotoxicity and that damage occurs rapidly. DCPT primarily affects the liver and may be a useful compound to investigate the role of the TZD ring in hepatic injury. However, the gender dependency and rapid onset of DCPT hepatotoxicity require further investigation.

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

“…Even among the DCBs, toxicity is dependent on the chlorine substitution pattern, with 1,2-DCB producing the largest elevations in serum ALT levels at comparable doses of the three isomers (Stine et al, 1991;Valentovic et al, 1993). Furthermore, ALTs were elevated by 0.4 mmol/kg DCPT (Patel et al, 2008), whereas 4 mmol/kg 1,3-DCB produced no such effect (Valentovic et al, 1993). Collectively, these findings suggest that hepatotoxicity is primarily due to the TZD ring, not the 1,3-DCB moiety, of DCPT.…”

“…As part of a structure-activity relationship study into the mechanism of toxicity for these types of compounds, we discovered that DCPT produced hepatotoxicity in male Fischer 344 rats (Kennedy et al, 2003). The liver damage associated with DCPT was subsequently found to be dose-, time-and gender-dependent (Patel et al, 2008). DCPT-induced hepatotoxicity was characterized by centrilobular necrosis, hepatocyte swelling, nuclear condensation and elevated serum alanine aminotransferase (ALT) levels.…”

“…DCPT-induced hepatotoxicity was characterized by centrilobular necrosis, hepatocyte swelling, nuclear condensation and elevated serum alanine aminotransferase (ALT) levels. In contrast, DCPT had only mild toxic effects on rat kidney function and morphology (Kennedy et al, 2003;Patel et al, 2008).…”

“…This is due, at least in part, to the fact that the glitazones are not hepatotoxic in any common laboratory animal species (Smith, 2003;Chojkier, 2005;Ong et al, 2007). Since it produces liver damage in rats (Kennedy et al, 2003;Patel et al, 2008) DCPT may be a useful model compound to explore the potential role of a TZD ring in chemically-induced hepatotoxicity. However, it should be noted that the substitution pattern in the TZD ring of DCPT differs from that in the glitazones (Fig.…”

“…We were therefore interested in determining if biotransformation could have a similar role in DCPTinduced liver damage. Previously, we found that DCPT was less hepatotoxic in female versus male rats, which could be due to a gender-based difference in metabolism (Patel et al, 2008). The centrilobular nature of DCPT-induced liver damage (Kennedy et al, 2003;Patel et al, 2008) suggests that hepatic CYPs may be involved in DCPT metabolic activation (Lindros, 1997).…”