Journal Article

Neoplastic transformation and DNA-binding of 4, 4'-methylenebis (2-chloroaniline) in SV40-immortalized human uroepithelial cell lines

Santhanam Swaminathan, Susan M. Frederickson, James F. Hatcher, Catherine A. Reznikoff, Mary A. Butler, Kenneth L. Cheever and Russell E. Savage

in Carcinogenesis

Volume 17, issue 4, pages 857-864
Published in print April 1996 | ISSN: 0143-3334
Published online April 1996 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.4.857
Neoplastic transformation and DNA-binding of 4, 4'-methylenebis
                    (2-chloroaniline) in SV40-immortalized human uroepithelial cell
                    lines

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The tumorigenic transformation of certain occupationally significant chemicals, such as N-hydroxy-4, 4'-methyl-enebis[2-chloroaniline] (N-OH-MOCA), N-hydroxy-ortho-toluidine (N-OH-OT), 2-phenyl-1, 4-benzoquinone (PBQ) and N-hydroxy-4-aminobiphenyl (N-OH-ABP) were tested in vitro using the well established SV40-immortalized human uroepithelial cell line SV-HUC.PC. SV-HUC cells were exposed in vitro to varying concentrations of N-OH-MOCA, N-OH-OT, N-OH-ABP and PBQ that caused approximately 25% and 75% cytotoxicity. The carcinogen treated cells were propagated in culture for about six weeks and subsequently injected subcutaneously into athymic nude mice. Two of the fourteen different groups of SV-HUC.PC treated with different concentrations of N-OH-MOCA, and one of the three groups exposed to N-OH-ABP, formed carcinomas in athymic nude mice. 32P-postlabeling analyses of DNA isolated fromSV-HUC.PC after exposure to N-OH-MOCA revealed one major and one minor adduct. The major adduct has been identified as theN-(deoxyadenosin-3',5' -bisphospho-8-yl)-4-amino-3-chlorobenzyl alcohol (pdAp-ACBA) and the minor adduct as N-(deoxyadenosin-3', 5'-bisphospho-8-yl)-4-amino-3-chlorotoluene (pdAp-ACT). Furthermore, SV-HUC.PC cytosols catalyzed the binding of N-OH-MOCA to DNA, in the presence of acetyl-CoA, to yield similar adducts. The same adducts were also formed by chemical interaction of N-OH-MOCA with calf thymus DNA, suggesting that the aryl nitrenium ion may be the ultimate reactive species responsible for DNA binding. The tumorigenic activity of N-OH-MOCA in this highly relevant in vitro transformation model, coupled with the findings that SV-HUC.PC cells formed DNA-adducts in vitro and contained enzyme systems that activated N-OH-MOCA to reactive electrophilic species that bound to DNA, strongly suggest that MOCA could be a human bladder carcinogen. These findings are consistent with the International Agency for Research on Cancer's classification of MOCA as a probable human carcinogen.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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