Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the influence of ethanol on human cancer incidence.

Abstract

Alcohol consumption is associated with an increase in human cancer, notably of the oesophagus. We have found that ethanol will alter profoundly the distribution of two carcinogenic nitrosamines in the rat. Small oral doses of dimethylnitrosamine (NDMA) are absorbed from the portal blood as it passes through the liver, and do not reach the extrahepatic organs. Ethanol, equivalent to a man drinking 1 pint (0.5 l) of beer, prevents this first pass clearance in the rat and exposes sensitive extrahepatic organs to this carcinogen. As a consequence the alkylation of kidney DNA by 35 micrograms NDMA/kg body weight was increased 4.6-fold by concurrent administration of 240 mg ethanol/kg, and smaller doses of [14C]-NDMA produced detectable alkylation of kidney DNA only if the rats were given ethanol. Measurement of metabolism of NDMA by liver slices confirmed that this action of ethanol is the result of inhibition by ethanol of NDMA metabolism in liver (Ki = 0.5 mM). Comparison of urinary excretion in man and rat suggests that ethanol also inhibits first pass clearance of NDMA in man. There was no complete first pass clearance of diethylnitrosamine (NDEA), but while ethylation of kidney DNA was decreased by ethanol, that of oesophageal DNA was increased between 1.8- and 4.6-fold. Measurement of the metabolism of NDEA to CO2 by liver slices, kidney slices, and oesophageal epithelium suggest that the changes in alkylation of kidney and oesophageal DNA are the result of selective inhibition of NDEA metabolism in liver and kidney. The ethylation of oesophageal DNA was greater relative to liver after a small dose than after a large dose possibly because of the low Km of the oesophageal metabolic activating system relative to that in liver and kidney. These results explain experiments showing that concurrent administration of ethanol increases the carcinogenicity and alters the organs affected by these nitrosamines. It is tentatively proposed that the effect of ethanol on human cancer incidence is mediated through similar influences on the metabolism and disposition of the nitrosamines to which man is exposed.