ABSTRACT
We measured levels of N-nitrosodimethylamine (NDMA) in peripheral blood from 13 fasting male patients, 30-74 years old, who had chronic renal failure, and in five healthy control subjects (four males and one female) 31-50 years old. In the patients, we found significant (P less than .01) levels of NDMA (mean +/- SD; 201 +/- 111 ng/kg of blood), which is known to be carcinogenic in animals. Five minutes after oral administration of ethanol (0.4 g/kg of body weight), all patients exhibited a significant (P less than .01) rise in blood NDMA levels (338 +/- 125 ng/kg), suggesting continuous endogenous formation of NDMA that was unmasked by ethanol's ability to inhibit first-pass hepatic metabolism of NDMA. In five of six patients, pretreatment with oral ascorbic acid resulted in a blunting, but not statistically significant, effect on maximum blood NDMA levels after consumption of ethanol. Mean levels were 340 +/- 100 ng/kg before treatment with ascorbic acid and 237 +/- 127 ng/kg during treatment. Ethanol administration unmasks increased gastrointestinal formation of NDMA in patients with chronic renal failure. Further studies are required to confirm a possible link between endogenous NDMA formation and the increased incidence of cancer in these patients.
Subject(s)
Ascorbic Acid/pharmacology , Dimethylnitrosamine/metabolism , Ethanol/pharmacology , Kidney Failure, Chronic/blood , Adult , Aged , Analysis of Variance , Digestive System/drug effects , Digestive System/metabolism , Female , Humans , Liver/drug effects , Liver/metabolism , Male , Middle AgedSubject(s)
Dimethylnitrosamine/metabolism , Kidney Failure, Chronic/metabolism , Administration, Oral , Adult , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Ascorbic Acid/pharmacology , Duodenum/analysis , Female , Humans , Liver/metabolism , Male , Middle Aged , Stomach/analysisABSTRACT
We have demonstrated that patients with chronic renal failure generate increased amounts of both dimethylamine and N-nitrosodimethylamine in the small bowel in association with aerobic and anaerobic bacterial overgrowth. The significance of these findings in relation to the reported increased incidence of cancer in patients with chronic renal failure has not yet been defined.
Subject(s)
Duodenum/metabolism , Kidney Failure, Chronic/metabolism , Nitroso Compounds/metabolism , Chromatography, Gas , Dimethylamines/metabolism , Dimethylnitrosamine/metabolism , Humans , Kidney Failure, Chronic/blood , Nitrosamines/metabolismABSTRACT
We have previously reported raised concentrations of dimethylamine and also bacterial overgrowth in the small intestine in CRF. Evidence for in vivo NDMA formation in the same site in CRF is now presented. Gastroduodenal intubation was performed in 9 healthy volunteers and 7 patients with advanced chronic renal failure. Blood, gastric, and duodenal aspirates were analyzed for NDMA. NDMA levels in control and CRF patients for blood were normal, but for gastric aspirate they were 67 +/- 13 and 312 +/- 68 (P less than 0.001) and for duodenal aspirate they were 70 +/- 21 and 319 +/- 47 (P less than 0.001), respectively. The results of bacterial cultures confirmed small intestinal bacterial overgrowth. We thus demonstrated statistically significant differences between NDMA concentrations in the control subjects and patients for both gastric and duodenal aspirates. This suggests that there is increased intestinal generation of NDMA in uremia. The presence of this precarcinogen may be linked with the reported increase in the incidence of cancer in CRF.
