Relationships between metabolic deactivation of ICR compounds and their differential mutagenicity in bacteria and cultured mammalian cells.

Preparations of Chinese hamster ovary (CHO) cells decreased the genotoxicity of 3 ICR compounds (ICR 191, ICR 191-OH and ICR 170-OH), while they did not affect the genotoxicity of ICR 170 in the Salmonella reversion test nor in a DNA-repair test in E. coli. These data may contribute towards the explanation of the lack of activity of the two hydroxylated compounds in the CHO/HGPRT forward mutation system, as well as the different rank of mutagenicity of the two chloroethyl compounds in bacteria (ICR 191 greater than ICR 170), compared to cultured mammalian cells and in general to eukaryotic cells (ICR 170 greater than ICR 191).

Selective deactivation of ICR mutagens as related to their distinctive pulmonary carcinogenicity.

The mutagenicity patterns and the metabolic behaviour of 4 structurally related ICR compounds were investigated using the Salmonella/microsome test. ICR 191 and ICR 170 reverted 4 his- strains (TA1537 greater than TA100 greater than TA98 and TA1538), while ICR 191-OH and ICR 170-OH reverted TA1537 only, with a narrow range of mutagenic activity. Although all the products tested were shown to contain a common mutagenic impurity, analysis of chemicals fractionated by h.p.l.c. provided evidence that pure ICR 191-OH and ICR 170-OH also induce frameshift errors. The mutagenic activity of all the 4 ICR compounds, as well as of their common impurity, was decreased in the presence of S-9 mix containing rat liver S-9 fractions, a trend confirmed by h.p.l.c. of ICR/S-9 mixtures. Despite the greater mutagenic potency in the absence of metabolic systems, ICR 191 was deactivated far more efficiently and rapidly than ICR 170 by a variety of mouse (liver greater than lung) and rat (liver greater than testis greater than kidney greater than lung greater than striated muscle greater than spleen) S-9 fractions. Mouse preparations were more effective than the corresponding rat preparations. Aroclor 1254 strongly stimulated tha activity of th NADPH-requiring enzymes responsible for ICR deactivation. H.p.l.c. analyses ruled out interconversion among the 4 ICR compounds in the presence of liver S-9 fractions, while revealing the appearance of new distinct peaks for ICR 191, ICR 170 and ICR 170-OH. The selective metabolic deactivation of ICR compounds may be related to the findings of previous carcinogenicity studies (1-3) which showed the induction of lung adenomas following i.v. but not i.p. administration of ICR 170. Conversely, ICR 191 and ICR 191-OH showed no activity even when administered i.v. Since intercalation of ICR compounds into DNA is the molecular basis for both mutagenic and antitumor activities (4), their distinctive metabolic reactivity may be also responsible for the differential efficacy in pharmacological assays.