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Characterization of 4,4'-methylenebis(2-chloroaniline) -- DNA adducts formed in vivo and in vitro.
Segerback D; Kadlubar FF
Carcinogenesis 1992 Sep; 13(9):1587-1592
DNA adducts formed with 4,4'-methylenebis(2-chloroaniline) (101144) (MOCA) both in-vivo and in-vitro were characterized. Male Charles- River-rats were given a single intragastric dose of 10mg/ml radiolabeled MOCA at a dose rate of 95 micromoles per kilogram body weight. Rats were killed at 1, 3, 7, or 21 days, and DNA was isolated from livers, lungs, and kidneys. For structural studies, DNA was treated with N-hydroxy-MOCA. Adducts were analyzed using high performance liquid chromatography (HPLC) and fast atom bombardment mass spectrometry. Results showed two major peaks (about 80% of total DNA binding) on HPLC separation of samples from enzymatic hydrolysis of DNA treated with N-hydroxy-MOCA. Although the radioactivity associated with the two products was ten times higher after 24 hours (hr) than after 1hr, the adduct pattern was identical. The two products were identified as N-(deoxyadenosin-8- yl)-4-amino-3-chlorobenzyl-alcohol and N-(deoxyadenosin-8-yl)-4- amino-3-chlorotoluene. The ultraviolet spectra of the two major adducts from all the organs studied from MOCA treated rats were very similar. Both adducts showed similar nonlinear elimination kinetics. The authors conclude that an intact MOCA-adenine adduct is unstable and would result in decomposition through ring cleavage to 2-chloroaniline and a quinonemethide intermediate that could hydrolyze or undergo reduction. While N-hydroxy-MOCA itself could serve as the reducing agent in the in-vitro reactions, the reducing agent in the in-vivo situation is not known.
NIOSH-Publication; NIOSH-Contract; Contract-224-88-0003; Anilines; Carcinogens; DNA-adducts; Laboratory-animals; Metabolism; Molecular-structure; In-vitro-studies; In-vivo-studies
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