Further characterization of the ability of hepatocarcinogens to lower rat liver aryl sulfotransferase activity

Abstract

Aryl sulfotransferase (AST) activity in rat liver is thought to be a primary pathway in the bio-activation of various hepatocarcinogens to forms which act as ultimate carcinogens in chemical hepatocarcinogenesis. In an effort to understand the significance of rapid and sustained decreases in liver AST that accompany dietary administration of hepatocarcinogens and to further assess its relationship to carcinogenic processes, we determined the abilities of various xenobiotics known to be hepatocarcinogens or non-hepatic carcinogens to lower AST activity. We also determined whether the co-administration of the AST enzyme inhibitor, pentachlorophenol, with hepatocarcinogens will abrogate the lowering of AST activity caused by hepatocarcinogens which do not utilize AST for bio-activation versus hepatocarcinogens which can utilize AST. Among carcinogens tested thus far, we have found the AST activity of liver cytosols to be lowered by the hepatocarcinogens 2-acetylaminofluorene, ethionine, 3'-methyl-4-dimethylaminoazobenzene, thioacetamide, aflatoxin B1, diethylnitrosamine and benzidine, but not by the non-hepatic carcinogens 2-acetylaminophenanthrene or 3-methylcholanthrene. Pentachlorophenol reversed activity losses when co-administered with all carcinogens which lowers AST activity with the exception of ethionine and thioacetamide. We suggest that AST activity lowering is relatively specific for liver carcinogens and involves two different mechanisms.

Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

“…Another factor is inhibition of AST activity, which was measured in the liver cell cytosol. Previous reports, at doses greater than seven times the present HE of AAF, reported inhibition of this enzyme (Ringer and Norton, 1987). In the present study, inhibition occurred with the top two exposures.…”

“…AST activities were determined at 12 weeks as described by Mulder et al (1977) and Ringer (1987). The liver homogenates were centrifuged at 9000g for 20 min to remove nuclei, lysosomes, and mitochondria, and the supematants were then centrifuged at 100,000g for 60 min to sediment the microsomes.…”

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

“…At the next cumulative exposure level (43 mg/kg at 4 weeks, 87 mg/kg at 8 weeks, and 130 mg/kg at 12 weeks), the liver changes, that is, LBR and DNA adduct formation, were very similar in magnitude to the lower exposures up to week 12. DNA adduct formation was greater, achieving 91% of that of the magnitude of the high exposure, and arylsulfotransferase activity, the nal enzymatic step in AAF bioactivation (106), was inhibited and the centrilobular glutamine synthetase expressing zone was reduced, indicating cytotoxicity. This exposure produced a low level of promotable initiation (one adenoma).…”

Modulations of hepatic gamma-glutamyltranspeptidase and N-hydroxy-N-2-fluorenylacetamide sulfotransferase activities following treatment of rats with a hepatocarcinogenic regimen: effect of partial hepatectomy.

“…The levels of hepatic y-GTP and N-OH-2-FAA ST activities assayed on days 3, 17, 31, 66, and 87 (including nodules) after completion of 2-FAA treatment are shown in Figures 2 and 3, respectively. y-GTP activity determined 3 days after completion of 2-FAA treatment showed significant increases, 9.5-and 7.4-fold, respectively, in the livers of both -PH and +PH rats. On day 17 after the treatment, the enzyme activity in the -PH rats had returned to the control level but was 3.1-fold above the control level in the livers of +PH rats. On days 31, 66, and 87 after treatment with 2-FAA, y-GTP activity had increased only 1.4-to 2.6-fold in the livers of -PH rats; whereas, it had increased 15-to 32-fold in the livers of +PH rats.…”

“…After washing with icecold saline, livers were homogenized in 4 volumes of 50 mM Tris-HCl 154 mM KCl buffer, pH 7.4, as described previously (14). Whole (17). Briefly, in a final volume of 0.5 ml, p-nitrophenylsulfate (10 mM), 3',5'-adenosine diphosphate (0.02 mM) in 100 mM Tris-HCl buffer, pH 8.0, 0.3 mg cytosolic protein, and the acceptor substrate, N-OH-2-FAA (0.55 mM) in ethanol (5%), were mixed in a cuvette, and the increase in absorbance ofpnitrophenol at 405 nm (£, 18,380 M-cm-) was recorded every 30 sec at 31°C for 10 min, during which time the rates were linear.…”