Pinto, Luis Felipe Ribeiro; (1994) Nitrosamines and oesophageal cancer. A study of factors influencing the distribution and metabolism of nitrosamines and the enzymes responsible for their activation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Nitrosamines produce cancer in most species and possess remarkable organ specificity. Because they are the only carcinogens which can produce oesophageal tumours in experimental animals, and because all humans are exposed to them, it has been suggested that they produce oesophageal cancer in man. The organotropism of nitrosamines depends largely on the distribution of the nitrosamine and the P450s capable of metabolizing it in the animal body. Ethanol consumption, the main factor associated with oesophageal cancer in the West, changes the pharmacokinetics of nitrosamines, increasing the damage to extrahepatic organs, in particular to the oesophagus, and it has been suggested that these changes are responsible for the effect of ethanol on human oesophageal cancer. The influence of two factors associated with a high incidence of oesophageal cancer, opium (and morphine the major alkaloid found in opium), and isoamyl alcohol, a contaminant of Calvados, on the pharmacokinetics of N-nitrosodimethylamine and N- nitrosodiethylamine was investigated through measurement of their influence on the organ to organ distribution of alkylation produced by these nitrosamines, inhibition of the metabolism of these nitrosamines in vitro, and with isoamyl alcohol, its influence on reactions metabolized by different P450s. Morphine and opium dramatically change the pharmacokinetics of NDMA and NDEA, with inhibition of first pass clearance of NDMA and a shift of the metabolism of NDEA from the liver to the oesophagus. Although the mechanisms of these changes has have not been completely elucidated, the results are very similar to those previously obtained with ethanol. However, although isoamyl alcohol inhibited the general metabolism of NDEA in the rat, it did not affected its organotropism, and affects a broader range of P450s than ethanol. The oesophageal monooxygenase system was investigated in depth and compared to the liver through administration of chemicals which induce P450s in the liver, spectrophotometric measurements of the components of the monooxygenase system, western blot analysis of these components and particular forms of P450s, the capacity of oesophageal microsomes to metabolize different compounds, and the influence of nitrosamines on the metabolism of these compounds. The presence of P450 1A1, but not 2E1 or 2B1 and 2B2 in the oesophagus together with evidence that P450 1A1 can participate in the metabolism of N-nitrosomethylbenzylamine, the most powerful oesophageal carcinogen in the rat, is suggested to be one of the factors contributing to the organotropism of some nitrosamines for that organ.

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