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Neoplastic transformation and DNA-binding of 4,4'-methylenebis(2- chloroaniline) in SV40-immortalized human uroepithelial cell lines.
Swaminathan-S; Frederickson-SM; Hatcher-JF; Reznikoff-CA; Butler-MA; Cheever-KL; Savage-RE Jr.
Carcinogenesis 1996 Apr; 17(4):857-864
The neoplastic transformation and DNA binding potential of N-hydroxy- 4,4'-methylenebis(2-chloraniline) (NOHMOCA), N-hydroxy-o-toluidine (611223) (NOHOT), and 2-phenyl-1,4-benzoquinone (PBQ) were studied in SV40 immortalized uroepithelial cells. The compounds were derivatives of the putative bladder carcinogens 4,4'-methylenebis(2- chloroaniline) (101144) (MOCA), o-phenylphenol (90437), and o- toluidine (95534). SV-HUC.PC and SV-HUC.BC cells were incubated with NOHMOCA, NOHOT, or PBQ for 24 hours (hr). The cells were propagated by reseeding into new cultures for 6 weeks. They were then used to inoculate subcutaneously female athymic-nude-mice. Mice were observed weekly for tumor development. The mice were killed after 9 months and the tumors were excised for histological examination. Two sets of SV-HUC.PC cells treated with NOHMOCA induced tumors in nude mice. The NOHMOCA induced tumors were poorly differentiated carcinomas. PBQ and NOHOT treated SV-HUC.PC cells did not induce any tumors. None of the treated SV-HUC.BC cells induced tumors following inoculation into nude mice. NOHMOCA was studied additionally by adding it to SV-HUC.PC cells for 24hr, after which the DNA was extracted and examined for adducts by phosphorus- 32 post labeling. A similar experiment was performed in which NOHMOCA was reacted with calf thymus DNA in the presence or absence of SV-HUC.PC cell cytosol and acetylcobalamine-A (AcCoA). NOHMOCA was bound to SV-HUC.PC cellular DNA and formed one major and one minor adduct. The same adducts were formed following reaction of NOHMOCA with calf thymus DNA and SV-HUC.PC cytosol + AcCoA. The authors conclude that NOHMOCA induces neoplastic transformation of nontumorigenic SV transformed human uroepithelial cells to tumorigenicity. The fact that NOHMOCA can be activated by cytosolic enzymes, possibly by acetyltransferases, to form electrophilic species that bind to DNA suggests that the parent compound MOCA is a human bladder carcinogen.
NIOSH-Author; In-vitro-studies; Mammalian-cells; Humans; Neoplastic-transformation; Bladder-cancer; DNA-adducts; In-vivo-studies; Laboratory-animals; Tumorigenesis
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Page last reviewed: April 12, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division