THE LIVER PLAYS A CENTRAL ROLE IN THE MECHANISM OF CHEMICAL CARCINOGENESIS DUE TO POLYCYCLIC AROMATIC-HYDROCARBONS

The important problem of whether metabolites and DNA adducts from benzo[a]pyrene (B[a]P) originate in the liver or target tissues was assessed using orthotopic liver transplantation. Following liver transplantation, the only source of metabolites for release into the blood and accumulation in target tissues is the liver. [H-3]B[a]P (4-mu-M, 5 Ci/mmol) was infused into the portal vein of rats, and livers were perfused and either transplanted to a second rat or sham-operated and left in situ (non-transplant group). After 4 h, seven organs were collected and polar metabolites and DNA adducts were measured. In both groups, B[a]P in blood samples was below the limits of detection while levels of B[a]P in liver samples were approximately 5 pmol/g and polar metabolites were approximately 10 pmol/g. Concentrations of polar metabolites were also nearly identical in peripheral tissues from both groups. Phenols, glucuronides, sulfates and an unidentified metabolite of B[a]P were also similar, but GSH conjugate(s) had a tendency to be lower in blood of animals with transplanted livers. DNA adducts ranged from minimal values near levels of detection to approximately 0.2 pmol/mg DNA in lung, liver, and kidney. Importantly, there were no differences in DNA binding between the transplant and non-transplant groups. Taken together, these data provide compelling evidence that the liver is the predominant site of conversion of B[a]P into polar metabolites which are transported to target tissues and subsequently bind to DNA. Release of polar metabolites from the liver may represent a novel pathway for delivery of carcinogen conjugates to target tissues.