Jd Horton

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

Abstract 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.

Repeated estimation of liver cholesterol synthesis in vivo, using the inhibitor AY-9944.

Abstract 1. 1. We have examined the validity and usefulness of an assay for liver cholesterol synthesis using the inhibitor AY-9944, which inhibits only the conversion of 7-dehy-drocholesterol to cholesterol. 2. 2. In rats treated with a single dose of AY-9944 the level of 7-dehydrocholesterol in the blood 24 h after treatment is representative of the cholesterol which would have been synthesised by the liver had the inhibitor not been present. 3. 3. The assay has been tested under a variety of conditions known to alter liver cholesterol synthesis, and was found to correlate closely with values obtained when liver synthesis was measured in vitro. 4. 4. Consistent results were obtained with repeated assays, which can be carried out at weekly intervals on the same animals.

Metabolic controls in precancerous liver—V. Loss of control of cholesterol synthesis during feeding of the hepatocarcinogen 3′-methyl-4-dimethylaminoazobenzene

Abstract We have examined dietary control of cholesterol synthesis in rat liver during the feeding of 3 ′-methyl- 4 -dimethyl-aminoazobenzene ( 3 ′ MeDAB), using an assay which permits repeated tests on the same animal. Synthesis was measured as plasma levels of 7 -dehydrocholesterol following a single dose of AY- 9944 (trans 1,4-bis ( 2 -chlorobenzylaminomethyl) cyclohexane dihydrochloride), a drug which inhibits the conversion of 7 -dehydrocholesterol to cholesterol. During 3 ′ MeDAB feeding there was a significant loss of inhibition of sterol synthesis in response to cholesterol feeding, but control rapidly returned to normal as soon as the carcinogen treatment was discontinued. The loss of control observed here was similar to that previously reported for 3 other hepatocarcinogens.

Influence of the carcinogen 2‐acetylaminofluorene on rat feeding behaviour

Abstract The feeding pattern of rats fed the carcinogen 2‐acetylaminofluorene (AAF) ad libitum was investigated using a continuous‐recording electronic balance. Although a regular rhythm of eating was maintained, the timing of this rhythm was moved forward by 2–8 hrs. The extent of this shift increased with higher levels of dietary AAF, and with increasing time of AAF feeding. However, the degree of this change varied from rat to rat. As a result of the change in the timing of the diurnal rhythm of feeding, the rhythm of the AAF‐treated rats was no longer related to the controlled lighting conditions. There was also no relationship between the timing of the rhythm in any particular rat and the rhythms of rats in adjacent cages.