title: Inhibitory effect of benzene metabolites on nuclear DNA synthesis in bone marrow cells.
abstract: Effects of endogenously produced and exogenously added benzene metabolites on the nuclear DNA synthetic activity were investigated using a culture system of mouse bone marrow cells. Effects of the metabolites were evaluated by a 30-min incorporation of [3H]thymidine into DNA following a 30-min interaction with the cells in McCoy's 5a medium with 10% fetal calf serum. Phenol and muconic acid did not inhibit nuclear DNA synthesis. However, catechol, 1,2,4-benzenetriol, hydroquinone, and p-benzoquinone were able to inhibit 52, 64, 79, and 98% of the nuclear DNA synthetic activity, respectively, at 24 microM. In a cell-free DNA synthetic system, catechol and hydroquinone did not inhibit the incorporation of [3H]thymidine triphosphate into DNA up to 24 microM but 1,2,4-benzenetriol and p-benzoquinone did. The effect of the latter two benzene metabolites was completely blocked in the presence of 1,4-dithiothreitol (1 mM) in the cell-free assay system. Furthermore, when DNA polymerase alpha, which requires a sulfhydryl (SH) group as an active site, was replaced by DNA polymerase I, which does not require an SH group for its catalytic activity, p-benzoquinone and 1,2,4-benzenetriol were unable to inhibit DNA synthesis. Thus, the data imply that p-benzoquinone and 1,2,4-benzenetriol inhibited DNA polymerase alpha, consequently resulting in inhibition of DNA synthesis in both cellular and cell-free DNA synthetic systems. The present study identifies catechol, hydroquinone, p-benzoquinone, and 1,2,4-benzenetriol as toxic benzene metabolites in bone marrow cells and also suggests that their inhibitory action on DNA synthesis is mediated by mechanism(s) other than that involving DNA damage as a primary cause.
authors.affiliation: Biomedical Science Department, General Motors Research Laboratories, Warren, Michigan 48090-9055.
authors.forename: E W
authors.initials: EW
authors.lastname: Lee
authors.forename: J T
authors.initials: JT
authors.lastname: Johnson
authors.forename: C D
authors.initials: CD
authors.lastname: Garner
mesh_terms: D000818:Animals; D001554:Benzene / Q000378:metabolism* / Q000494:pharmacology; D016227:Benzoquinones; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002474:Cell-Free System / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006873:Hydroquinones / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors; D011809:Quinones / Q000494:pharmacology
chemical_list: D016227:Benzoquinones; D002396:Catechols; D006873:Hydroquinones; D019384:Nucleic Acid Synthesis Inhibitors; D011809:Quinones; C013038:hydroxyhydroquinone; C004532:quinone; D004247:DNA; D001554:Benzene; C034221:catechol; C031927:hydroquinone