Published in Cancer Detection and Prevention 1999; 23(2):107-115.

Presystemic Intestinal Metabolism of N-Nitrosodimethylamine

Johannes Schulze, P.D.Dr.

Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University, Munich, Germany

Address all correspondence and reprint requests to: P.D.Dr. Johannes Schulze, Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians Universität München, Nussbaumstrasse 26,D 80336 München, Germany.

ABSTRACT: N-Nitrosodimethylamine (NDMA), a common food contaminant, is a potent liver carcinogen in rodents. A high presystemic intestinal metabolism has been shown for several nitrosamines including environmentally important compounds. We determined the metabolism of 1 (m [14C]-NDMA in isolated perfused mouse intestinal segments. We found NDMA to be equally distributed between the absorbed fluid and the perfusate. During a 2-h perfusion period, 0.13% of the radioactivity was convened to CO2. The formation of CO2 was decreased by pretreatment with diallylsulfide or addition of SKF 525A, and slightly increased by phenobarbital. Hydrophilic metabolites were found in the absorbate (0.9%) and perfusate (3.8%) of untreated mice. The amount of metabolites in the absorbate was increased by treatment with acetone or phenobarbital (8-fold), but not after starvation, with formaldehyde being present only in phenobarbital-treated animals. Treatment with diallylsulfide or addition of SKF 525A reduced the amount of metabolites in acetone-treated animals to control values. In conclusion, intestinal turnover does not significantly reduce the body burden of orally ingested NDMA and thus is not a first-line defense against this carcinogenic nitrosamine. NDMA metabolism has been attributed to the presence of cytochrome P450IIE1, which has not been detected in the intestine of untreated animals. The low turnover of NDMA, the induction by acetone and phenobarbital treatment, and the inhibition by diallylsulfide suggest the presence of low amounts of this or related cytochrome P450 isozyme(s) in mouse intestine.

KEY WORDS: intestine, metabolism, mouse, N-nitrosodimethylamine.