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HERO ID
2143199
Reference Type
Technical Report
Title
Inhibition of DNA Polymerase Alpha by PAH
Author(s)
Busbee, D; Joe, C; Norman, J; Sylvia, V
Year
1988
Report Number
NIOSH/00180794
Volume
A Decade of Progress
Page Numbers
A Decade of Progress
Abstract
Inhibition of DNA-polymerase-alpha (pol-A) by polynuclear aromatic hydrocarbons (PAHs) was studied in-vitro. Tritiated thymidine incorporation resulting from blastogenesis or unscheduled DNA synthesis (UDS) was studied in human peripheral blood lymphocytes, and inhibition of pol-A was studied using enzyme isolated from human lymphocytes (PBL) or cultured mouse sarcoma cells. Exposure of PBL to 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (58917672) (BPDE) decreased blastogenic synthesis in response to phytohemagglutinin (PHA) and in non mitogen stimulated cells. When DNA was isolated from cells, exposed to BPDE to form adducts, and used as template for pol-A activity, no difference in thymidine incorporation was observed in relationship to BPDE dose, suggesting that BPDE adducts did not inhibit pol-A activity. Lineweaver Burke type analysis suggested that BPDE bound pol-A in an inhibitory fashion after the enzyme bound an initial DNA template. Similar experiments using 8,9-dihydroxy-10,11-epoxy-8,9,10,11-tetrahydrobenz(a)anthracene showed a comparable type of inhibition to that of BPDE, with competitive inhibition of deoxy-guanosine-monophosphate incorporation. Parent PAHs and partially activated diol forms were not inhibitory. A series of immunosuppressive corticosteroids were examined for pol-A inhibition. They were found to inhibit in a similar manner to adduct forming PAHs, depending on their structure. In contrast, methyl-methanesulfonate (66273) directly inhibited pol-A without a requirement for template binding. The authors conclude that inhibition of DNA synthesis presumed to be due to DNA adduct formation may be due to alteration of DNA pol-A.
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