Trichloroacetic acid: studies on uptake and effects on hepatic DNA and liver growth in mouse

Abstract

Trichloroacetic acid (TCA) was tested in mice for its ability to cause single-strand breaks (SSBs) in hepatic DNA in the presence and absence of liver growth induction. Male B6C3F1 mice were given 1, 2 or 3 daily doses of TCA (500 mg/kg p.o.) as a neutralized solution (sodium salt) and killed 1 h after the final dose. Some mice were given a single dose of TCA (500 mg/kg p.o.) as the acid or as a neutralized solution and killed 24 h after. Liver nuclei were prepared and the induction of DNA SSBs assayed. TCA gave no significant response. Absorption and distribution studies were conducted with radiolabelled trichloro[2-14C]acetic acid, which was administered by gavage (500 mg/kg) as aqueous free acid, neutral aqueous solution (sodium salt) or free acid in corn oil. The absorption and distribution of TCA was similar in all cases: the chemical was absorbed rapidly after dosing, maximum plasma and liver concentrations of free radiolabel being achieved in less than 1 h. Within the first 4 h following dosing there was no evidence of binding to DNA or other macromolecules in plasma and very little 'covalent' binding was detected in liver, indicating that at times when maximum DNA single-strand breakage has been reported there was no significant binding to liver cells. Studies on liver growth parameters (hyperplasia and peroxisome proliferation) with TCA revealed that the chemical induced small but significant increases in both parameters. No SSB induction was detected in association with either liver growth phenomenon elicited by TCA. We have thus found no evidence that TCA causes SSBs in the hepatic DNA of treated mice, in contrast to previous observations by other investigators.

Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes

“…The abilities of DCA and TCA to cause PPAR␣ activation, peroxisome proliferation, alteration in fatty acid and glycogen metabolism and a transient increase in hepatocyte proliferation are well documented Travis, 1993, 1994;Kato-Weinstein et al, 1998;Lingohr et al, 2002Lingohr et al, , 2001Maloney and Waxman, 1999;Stauber and Bull, 1997;Styles et al, 1991;Walgren et al, 2000a, b). However, the relationship between these early effects and the subsequent development of hepatocellular carcinoma is not understood.…”

“…This increase is followed by a long-term generalized decrease in hepatocyte DNA synthesis and development of focal areas with sustained high levels of replication ("preneoplastic foci"; Travis, 1993, 1994;Stauber and Bull, 1997;Styles et al, 1991). It has been suggested that the initial transient increase in hepatocyte replication could result in enhanced expression of pretransformed cells in the liver, with subsequent development of liver tumors (Eacho et al, 1991;Kraupp-Grasl et al, 1991;Marsman et al, 1988).…”

Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.

“…Early reports indicated that TCA induced SSBs in the hepatic DNA of mice and rats (28,107). Subsequent experiments using the same methodology (108) failed to replicate the increase in SSBs observed in mice, using a single, high 500 mg/kg dose. Using slightly different methodology, Chang et al (109) found a very small but statistically significant increase in SSBs with a dose of 1,600 mg/kg TCA to mice but no effect at 800 mg/kg.…”

Novel Panel of Early Diagnostic Markers for Experimental Hepatocellular Carcinoma

“…Co. ARE) and rats were given TCA by gavages as 500 mg/kg /day for 5 days [8]. TCA was chosen because it has been reported to increase liver growth, cell proliferation, and lipid peroxidation in mice[7; [9][10][11]. All other chemicals used are of analytical grade obtained from Sigma (USA).…”