Abstract:
:Carbamoylation reactions of N-methyl-N'-aryl-N-nitrosoureas (I-X: X = -OCH3, -CH3, -H, -Cl, and -COCH3) and of their corresponding phenyl isocyanates (II-X: X = -OCH3, -CH3, -H, -Cl and -COCH3) to the amino group of 5'-amino-5'-deoxythymidine have been kinetically studied in a PBS. The pseudo-first-order rate constants (kc x 10(4) s-1, 37 degrees C) are 9.21 for I-OCH3, 5.11 for I-CH3, 20.1 for I-H, 3.45 for I-Cl and 5.75 for I-COCH3. These rate constants correlated well with the tumorigenic potency of I-X to mouse skin (r = 0.761), but did not correlate with the other factors [solvolytic reactivity, alkylating activity to 4-(p-nitrobenzyl)pyridine, and mutagenicity on Salmonella typhimurium TA1535]. When the rate ratio (kc/ks) of the carbamoylation (kc) with the solvolysis (ks) was compared with the tumorigenic potency, a much better correlation was found between them (r = 0.876). Since II-X were too reactive to measure their kinetic data, the extent of their reactions at the 60 min time point was compared with the reactions of I-X. The reactivity of II-X (II-OCH3 greater than II-CH3 greater than II-H greater than II-Cl greater than II-COCH3) did not correlate with that of I-X (I-H greater than I-OCH3 greater than I-CH3 greater than I-Cl greater than I-COCH3), but both I-X and II-X gave the same carbamoylated and solvolysis products. The present results suggest that carbamoylation of amino groups in cellular constituents by N-nitrosoureas is a critical factor in inducing mouse skin tumors by the agents and that the generated isocyanates may not be the key intermediates for the carbamoylation reactions.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Yano Kdoi
10.1093/carcin/13.4.699keywords:
subject
Has Abstractpub_date
1992-04-01 00:00:00pages
699-702issue
4eissn
0143-3334issn
1460-2180journal_volume
13pub_type
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