Bioactivation of asymmetric N-dialkylnitrosamines in rat tissues derived from the ventral entoderm.
Aliphatic methylalkylnitrosamines with a chain length of three to six carbon atoms are powerful oesophageal carcinogens in rats and have been shown to methylate target organ DNA preferentially. This class of carcinogens is efficiently metabolized not only in the oesophageal mucosa but also in the mucosa of the nasal and oral cavity, trachea and bronchioli, i.e., tissues derived from the rat ventral entoderm. In order to determine whether more than one cytochrome P450 isozyme is involved in the bioactivation of asymmetrical aliphatic dialkylnitrosamines in these tissues, we have studied the effects of various modulators of nitrosamine metabolism, including dietary zinc deficiency, ethanol and disulfiram, on DNA alkylation by N-nitrosomethyl-n-butylamine (NMBA) and its ethyl analogue N-nitrosoethyl-n-butylamine (NEBA). Formation of O6-methyl- and O6-ethyldeoxyguanosine by a single dose of NMBA and NEBA, respectively, was quantified after a survival time of 6 h by immuno-slot-blot assay. In control rats, methylation of DNA by NMBA was highest in oesophagus, followed by nasal mucosa, liver and lung. Formation of O6-ethyldeoxyguanosine from NEBA, however, was twice as high in liver as in nasal mucosa and lung and four times as high in liver as in oesophagus. In oesophagus, trachea and bronchioli, both nitrosamines were selectively metabolized in mucosal cells. Bioactivation of NMBA and NEBA was almost completely inhibited in nasal mucosa by ethanol. In contrast, a striking interorgan shift in DNA methylation by NMBA from liver (-50%) to lung (+100%), oesophagus (+300%) and nasal mucosa (+400%) was obtained with dietary disulfiram, whereas only 20-50% increases in extrahepatic DNA ethylation were determined for NEBA.(ABSTRACT TRUNCATED AT 250 WORDS)
Ludeke
B
B
Institute of Pathology, University of Zurich, Switzerland.
Meier
T
T
Kleihues
P
P
D000478:Alkylation; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology; D008297:Male; D009602:Nitrosamines / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009602:Nitrosamines; C025033:N-amyl-N-methylnitrosamine; C034649:nitrosomethyl-N-butylamine; D004247:DNA; D004221:Disulfiram