Histochemical findings suggesting that methylazoxymethanol, a liver and kidney carcinogen, is a substrate for hepatic and renal choline dehydrogenase.

Methylazoxymethanol (MAM) is a potent carcinogen and induces tumors predominantly in rat liver, colon and kidney. The findings reported in this paper suggest that MAM is a substrate for the enzyme choline dehydrogenase located in rat hepatocytes and in the terminal portion of the renal proximal convoluted tubule. As with the natural substrate choline, this reaction with MAM did not require NAD+, was not inhibited by pyrazole and was dependent on the electron transfer reagent, phenazine methosulfate. The product of this reaction is probably the same as that obtained from the metabolism of MAM by alcohol dehydrogenase, namely, an unstable aldehydic derivative which decomposes rapidly to carbonium ions. The reaction with alcohol dehydrogenase offered an explanation for the organotropic effects of this carcinogen in liver and colon and the current report provides a mechanism for the induction of kidney tumors as well as another possible means for production of liver tumors.

Drug-resistant Leptomonas: cross-resistance in trypanocide-resistant clones.

A Leptomonas of insect origin was highly susceptible to several standard trypanocides and leishmanicides in vitro. Resistance was induced to some of these drugs; clones were isolated from each strain. Cross-resistance patterns of the clones were derived for diamidines, quinapyramine (Antrycide), acriflavin, phenanthridines, and other drugs active against trypanosomes and leishmanias. Clones tested included two each that were resistant to acriflavin, Antrycide, diminazene aceturate (Berenil), and pentamidine and one that was resistant to stilbamidine. Appreciable cross-resistance was evident for all clones. Differences were observed between clones from the same parent strain. Collateral susceptibility towards isometamidium and oxophenarsine was detected in most clone-derived populations. In clones passaged without drug to test for drug fastness, acriflavin and pentamidine clones lost resistance within 10 transfers, whereas Berenil and Antrycide clones retained considerable resistance after 20 to 30 subcultures without drug. Considerations of differences in life cycles suggest that the clone collection may be useful in screening for agents effective against leishmanias and stercorarian trypanosomes rather than against salivary trypanosomes.