INFLUENCES OF CHRONIC CHOLANGIOHEPATITIS AND CHOLESTASIS ON HEPATIC-METABOLISM OF BENZO[A]PYRENE IN WHITE SUCKERS (CATOSTOMUS-COMMERSONI) FROM INDUSTRIALLY POLLUTED AREAS OF LAKE-ONTARIO

White suckers from polluted regions of western Lake Ontario have an in creased prevalence of cholangiocellular and hepatocellular neoplasms a ssociated with an idiopathic chronic cholangiohepatitis, We examined t he hypothesis that bile duct obstructions and cholestasis in these fis h might increase the susceptibility of liver to administered benzo[a]p yrene (B[alpha]P), Cytosolic glutathione S-transferase (GST) activity (CDNB) was reduced in obstructed liver to 45% of activity in adjacent unobstructed liver, At micromolar concentrations, chenodeoxycholic aci d, deoxycholic acid, bilirubin and haematin each inhibited GST activit y of hepatic cytosolic and S-hexylglutatione-affinity-purified GST pre parations from unobstructed liver, Liver cytosol and affinity-purified hepatic GSTs from normal white sucker liver reduced DNA binding of H- 3-benzo[alpha]-pyrene-7,8-diol-9,10-epoxide (H-3-BPDE) after preincuba tion in vitro in the presence of 5 mM GSH. Under these conditions, cyt osol from adjacent unobstructed liver had a moderately stronger protec tive activity against DNA binding by BPDE (16,4+/-1,3 pmol BPDE/mg DNA ) than did cytosol from obstructed liver (20,6+/-1,6 pmol BPDE/mg DNA) , Suckers with obstructed livers identified by laparotomy were orally administered 3H-benzo[a]pyrene (H-3-B[alpha]P) (0.2 mmol/kg) or unlabe lled B[alpha]P (2.0 mg/kg) and the level of B[alpha]P macromolecular b inding was analysed in liver tissue by liquid scintillation counting a nd by immunohistochemistry with antibodies to BPDE-DNA adducts, Covale nt binding of H-3-B[alpha]P to hepatic protein was 30% less in adjacen t unobstructed liver compared to obstructed liver; however, there was no significant difference in the levels of H-3-B[alpha]P bound to DNA in the obstructed lobes compared with non-obstructed adjacent liver, T hese studies demonstrate that some endogenous non-substrate ligands th at accumulate during cholestasis can reduce hepatic GST activity in wh ite suckers, While these changes are insufficient to influence total H -3-B[alpha]P-DNA adducts in obstructed liver, the preferential localiz ation of BPDE-DNA adducts in GST-deficient hyperplastic biliary tracts suggests that cholangiohepatitis might increase susceptibility to cho langiolar neoplasia in fish exposed to genotoxic polycyclic aromatic h ydrocarbons.