Metabolism of [14C]phenol in the isolated perfused mouse liver.

A previous report from this laboratory focused on the metabolism of [14C]benzene (BZ) in the isolated, perfused, mouse liver (C. C. Hedli, et al.

Investigation of hepatic cytochrome P-450 enzyme induction and DNA adduct formation in male CD/1 mice following oral administration of toxaphene.

Exposure of experimental animals to toxaphene induces hepatic cytochrome P-450 (CYP). Although chronic administration of toxaphene to mice was found to cause an increased incidence of liver tumors, a mechanism for its carcinogenicity has yet to be elucidated. We investigated two potential mechanisms of toxaphene-induced carcinogenicity: peroxisomal proliferation and DNA binding.

Benzene metabolism in the isolated perfused mouse liver.

The hematotoxicity of benzene (BZ) requires its hepatic metabolism, the release of metabolites into the circulation, and the access of metabolites to the bone marrow. Although a range of potentially toxic metabolites produced by the liver was identified using subcellular systems and isolated hepatocytes, these models do not allow identification of the metabolites released from the liver with respect to time and flow through the liver. We developed an isolated perfused mouse liver model to evaluate metabolites released following a single-pass of radiolabeled BZ and after recirculation of single-pass metabolites back through the liver.

An overview of benzene metabolism.

Benzene toxicity involves both bone marrow depression and leukemogenesis caused by damage to multiple classes of hematopoietic cells and a variety of hematopoietic cell functions. Study of the relationship between the metabolism and toxicity of benzene indicates that several metabolites of benzene play significant roles in generating benzene toxicity. Benzene is metabolized, primarily in the liver, to a variety of hydroxylated and ring-opened products that are transported to the bone marrow where subsequent secondary metabolism occurs.

Effects of benzene metabolite treatment on granulocytic differentiation and DNA adduct formation in HL-60 cells.

Reactive metabolites of benzene (BZ) play important roles in BZ-induced hematotoxicity. Although reactive metabolites of BZ covalently bind to DNA, the significance of DNA adduct formation in the mechanism of BZ toxicity is not clear. These studies investigated the covalent binding of the BZ metabolites hydroquinone(HQ) and 1,2,4-benzenetriol(BT) using the DNA [32P]postlabeling method and explored the potential relationship between DNA adduct formation and cell differentiation in human promyelocytic leukemia (HL-60) cells, a model system for studying hematopoiesis.