Carcinogen Metabolism with Human and Experimental Animal Tissues: Inter-individual and Species Differences

Abstract

Liver fractions obtained from surgery tissue samples of different human subjects were shown to convert vinyl chloride or related halo-olefins and several N-nitroso derivatives into alkylating and mutagenic intermediates. Although large inter-individual variations were observed, the average activity was in general lower or close to that of mouse or rat liver fractions. However, with N-nitroso-N'-methyl-piperazine, human liver samples were up to 40 times more active than rat liver. When hepatic benzo(a)pyrene (BP)-hydroxylase activity in samples from different human subjects was plotted against the liver microsome-mediated mutagenicity, a statistically significant positive correlation was obtained between the rates of oxidative BP-metabolism and mutagenicity in the presence of N-nitrosomorpholine or vinyl chloride as substrate. Such a correlation may have significance for developing methods to evaluate the drug- and carcinogen-metabolising capacity of different human individuals. Therefore, BP-hydroxylase activity in normal and tumorous lung tissue from 76 patients with lung tumours was measured. A 60-fold inter-individual variation was noted; in most cases the rates of BP-hydroxylation in tumorous lung tissue was lower than in normal tissue of the same patient. When BP-hydroxylase activity in the tumorous tissue (expressed as % activity of the normal tissue of the same patient) was plotted versusthe number of cigarettes smoked per day prior to surgery, a negative correlation was apparent. These interim results suggest that differences in carcinogenic metabolism may condition in part the response of human individuals when exposed to the same level of environmental carcinogens.