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Asbestos Increases Mammalian AP-Endonuclease Gene Expression, Protein Levels, and Enzyme Activity in Mesothelial Cells¹

Departments of Pathology [H. F., D. J. T., Y. M. W. J., B. T. M.], Microbiology and Molecular Genetics [Z. H.], and Medical Statistics [P. V.], University of Vermont, Burlington, Vermont 05405; Emory University, Department of Biology and Radiation Oncology, Atlanta, Georgia 30335 [Y. W. K.]; University of Texas Medical Branch at Galveston, Sealy Center for Molecular Science, Galveston, Texas 77555 [B. V. H.]; and Medical Research Council, Toxicology Unit, University of Leicester, Leicester, United Kingdom [S. P. F.]

Only two DNA repair enzymes, DNA polymerase ß and O⁶-methylguanine-DNA methyltransferase, have been shown to be inducible in mammalian cells by genotoxic agents. We show here that crocidolite asbestos induces the DNA repair enzyme, apurinic/apyrimidinic (AP)-endonuclease, in isolated mesothelial cells, the progenitor cells of malignant mesothelioma. Asbestos at nontoxic concentrations of 1.25 and 2.5 µg/cm² significantly increased AP-endonuclease mRNA and protein levels as well as enzyme activity (P < 0.05) in a dose-dependent manner in rat pleural mesothelial cells. These increases were persistent from 24 to 72 h after initial exposure to fibers. Changes were not observed with glass beads, a noncarcinogenic particle. Confocal scanning laser microscopy showed that AP-endonuclease was primarily localized in the nucleus but also in mitochondria. Our data are the first to demonstrate the inducibility of AP-endonuclease by a human class I carcinogen associated with oxidant stress in normal cells of the lung.

¹ This work was supported by NIEHS Grants ES07038 and ES06499.

² To whom requests for reprints should be addressed. Phone: (802) 656-0382; Fax: (802) 656-8892; E-mail: bmossman@zoo.uvm.edu.

Received 11/17/97. Accepted 12/11/97.

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