Lung and liver cell-mediated mutagenesis systems: specificities in the activation of chemical carcinogens

Abstract

A liver and lung cell-mediated-V79 cell mutagenesis system using intact cells as metabolic activation systems was employed to study the relative ability of cells from these organs to activate chemical carcinogens. Primary cultures of liver and lung cells from male Sprague Dawley rats were used to metabolically activate the chemicals and the mutation of Chinese hamster V79 cells to ouabain resistance used to detect mutagenic intermediates. 7,12-Dimethylbenz[a]anthracene and 3-methylcholanthrene, were more active in the lung system than in the liver cell system. Benzo[a]pyrene (B[a]P) was inactive in the liver cell-mediated system but mutagenic to V79 cells in the lung cell-mediated system. Dimethylnitrosamine (DMN) was inactive in the presence of lung cells but was mutagenic to V79 cells in the presence of liver cells. Aflatoxin B₁ was mutagenic in the liver cell-mediated system, but only weakly mutagenic in the lung cell-mediated system. Because the mutagenicities of DMN and B[a]P were organ-specific, the metabolism of these carcinogens in the two primary cell systems was investigated. DMN was metabolized by liver but not by lung cells, possibly accounting for its lack of mutagenicity in the lung cell system. B[a]P was extensively metabolized by both cell types, but quantitative differences were observed when the metabolic products were analyzed by high pressure liquid chromatography. Comparing total organic and water soluble metabolites, lung cells produced similar amounts of 7,8- and 9,10-diols but little 4,5-diol, while liver cells produced equivalent total amounts of the three diols. Lung cells produced twice the amount of B[a]P glucuronide conjugates as liver cells, while liver cells produced twice the amount of B[a]P sulfate conjugates as lung. The data suggest that intact cells from various organs can be used as metabolic activating systems in in vitro assays and that studies into organ specificity can be investigated by this approach.