Metabolic controls in precancerous liver—II: Loss of feedback control of cholesterol synthesis, measured repeatedly in vivo, during treatment with the carcinogens N-2-fluorenylacetamide and aflatoxin

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We have examined feedback control of cholesterogenesis in rat liver during the course of carcinogen treatment, using an assay for cholesterol synthesis which permits repeated tests on the same animal. Rats were treated with AY- 9944 (which inhibits the conversion of 7-dehydrocholesterol to cholesterol), and then 24 hr later blood levels of 7-dehydrocholesterol were measured. This gives an accurate estimation of liver sterol synthesis during that 24 hr period. By feeding 5% cholesterol for two days before each alternate assay, it was possible to measure feedback control of cholesterol synthesis for each individual animal during the carcinogen treatment. Rats injected with a single LD 50 dose of aflatoxin showed a severe loss of control of cholesterogenesis 3 to 5 weeks later. Most animals had recovered normal control 10 weeks after the aflatoxin treatment. N- 2-fluorenylacetamide feeding caused a similar marked loss of control within 1 to 2 weeks, and here also most animals regained normal control later. With both carcinogens the actual degree of loss of control of cholesterol synthesis was extremely variable between individual animals. Only a few animals showed complete loss of control and there was a wide range of varying degrees of partial control. Control of cholesterogenesis, as measured by two entirely independent assay systems, has now been shown to be defective after treatment with two different carcinogens, thus confirming the importance in the carcinogenic process, at least in the liver, of this loss of control previously known to occur in all fully-developed hepatomas.