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Groups of rats, either dosed with N-nitrosodiethylamine (NDEA) for 10 weeks (from the age of 7 to 17 weeks) or untreated, were fed diets containing either 2% (low fat, LF) or 30% polyunsaturated fat (high fat, HF) on an equicaloric basis from 5 weeks until rats were 43 weeks old. Biochemical parameters were measured during and at the end of the experiment in various organs, blood, urine and exhaled air, for correlation with the presence or absence of tumors. The HF diet tended to increase the number of hepatic tumors induced by NDEA, while the number of extrahepatic tumors was higher in rats fed on the LF diet; also the overall tumor incidence was higher in the LF group. In the HF/NDEA group, only two benign extrahepatic tumors were found. Plasma total and free cholesterol and triglyceride concentrations were lower in the HF than the LF group without NDEA treatment. In animals bearing liver and/or extrahepatic tumors all plasma lipid concentrations were lower than in tumor-free animals. Only minor or no changes were detected in blood catalase activity, malondialdehyde level, reduced glutathione (GSH) level or GSH-related enzymes and excretion of thioethers in the urine due to dietary modulation or NDEA. Changes in the liver that were associated with the HF diet were: (i) increased amounts of some polyunsaturated fatty acids and of total phospholipids in liver microsomes; (ii) an enhanced level of lipid peroxidation in liver; (iii) a decrease in liver glutathione levels during NDEA treatment, with a simultaneous adaptive increase in superoxide dismutase levels, and a decrease in renal glutathione levels in both treated and untreated groups; (iv) enhanced microsomal induction of aminopyrine N-demethylase and epoxide hydrolase activities by NDEA, and (v) decreased hexose monophosphate shunt (HMS) activity. All mono-oxygenase activities were lower, and the activities of epoxide hydrolase, UDP-glucuronosyltransferase and HMS were higher, in liver tumors than in non-tumorous liver of similarly-treated rats. Neither diet nor NDEA had a major effect on drug-metabolizing enzyme activities in lung and kidney. HF diet significantly increased ethane exhalation (an indicator of the whole-body pro-oxidant state) over those on the LF diet: in rats on either diet, it was further increased when NDEA was given. Ethane exhalation was still elevated 30 weeks after the cessation of NDEA treatment. Our results suggest an association between the observed changes in biochemical parameters, notably oxidative stress, due to dietary modulation and the altered tumor incidence and organ distribution of tumors induced by NDEA.

Since unsaturated fatty acids have been shown to control cell division experimentally the fatty acid composition in human mammary cancers as compared with the healthy surrounding tissue was studied. Both phospholipid and neutral lipid fractions were extracted for study and further lipid peroxidation expressed as thiobarbituric acid reactive substances was measured. For a comparison a benign adipose tissue tumor, lipoma, was studied. There was a 3.6-fold increase in phospholipid contents of cancer as compared with a reference tissue. No such differences were observed between lipoma and surrounding adipose tissue. In the phospholipid fatty acids of mammary cancers there was a marked increase in the relative amounts of unsaturated fatty acids, especially arachidonic acid, while saturated fatty acids were decreased, as compared with a healthy reference breast tissue or lipomas. The data suggest that the fatty acids might have a role in the development of breast cancer, possibly related to the formation of reactive metabolites of unsaturated fatty acids in the initiation of cancer or to their promotional effects.

In 32 women of normal body weight who volunteered to participate in the study, the effect of rapid weight reduction by a low-calorie liquid diet on serum lipids and lecithin:cholesterol acyltransferase (LCAT) enzyme activity was studied. Women were on this 400 kJ/day diet for 7 days and fasting blood samples were drawn before and immediately after the diet. Serum cholesterol decreased from 5.7 +/- 1.0 to 5.2 +/- 1.1 mmol/l and high density lipoprotein cholesterol from 1.77 +/- 0.43 to 1.50 +/- 0.35 mmol/l. The serum LCAT activity decreased significantly during the weight reduction period. When serum LCAT activity was correlated to lipid parameters, a positive correlation was found with total cholesterol and triglyceride concentrations before weight reduction and also between changes in LCAT activity and total cholesterol concentration. The data suggest that serum LCAT activity might have a prominent role in the regulation of serum lipid levels.

Serum lipids, postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activity, and furthermore adipose tissue LPL activity were studied in 20 middle-aged men undergoing a moderate training program of 15-wk. These same parameters were also measured in 7 nontraining control subjects. The training caused a significant (P less than 0.001) increase in physical fitness, and also considerable changes in serum lipid levels and lipolytic enzymes activities. In the trainers, serum HDL cholesterol increased by about 7% (P less than 0.01 and HDL/total cholesterol ratio by 11% (P less than 0.001). Decreases were observed in serum total (P less than 0.10 and LDL (P less than 0.05) cholesterol levels and in insulin values (P less than 0.05). No changes in these parameters occurred in the reference group. Postheparin plasma and adipose tissue LPL activity increased by 33% (P less than 0.001) and 56%, respectively, in the trainers. Postheparin plasma HL activity remained essentially the same in both groups, although a trend towards decreased values was seen in the trainers. On the other hand, postheparin plasma HL activity correlated negatively with serum HDL cholesterol levels both before and after the training period. The present results suggest that even with a moderate training program, beneficial effects on serum lipids in middle-aged men can be accomplished. There is also reason to believe that these changes are, at least in part, mediated by changes in the activities of lipolytic enzymes involved in lipoprotein metabolism, namely LPP and HL.

Thirty-five previously sedentary military conscripts, aged 19--20 years, were tested 1 week after entering the service and again 2 months later. In addition, 26 active sportsmen were studied. Physical working capacity (VO2 max), as judged by an ergometer stress test, improved significantly by about 31% during this period in the military conscripts. At the same time there was a significant increase in serum HDL cholesterol concentration and the HDL/total cholesterol ratio as total cholesterol did not change. An increase was found in serum triglyceride concentration. Serum lecithin: cholesterol acyltransferase (LCAT) activity increased due to the training period (p less than 0.01) and was related to changes in serum HDL cholesterol concentration. In the active sportsmen serum LCAT activity was significantly higher (p less than 0.001) than in conscripts before the training program, and the changes of LCAT activity correlated positively with changes in HDL cholesterol. The data suggest that the changes in serum lipids and lipoproteins during the physical activity are possibly mediated in part by serum LCAT activity.

Serum total cholesterol, HDL cholesterol, triglycerides, and adipose tissue lipoprotein lipase activity were analyzed in seven hypertensive subjects using 160-480 mg sotalol daily, before and after a 3-week pause in the treatment. Triglycerides decreased and HDL cholesterol increased significantly during the break in sotalol treatment, whereas no changes occurred in total cholesterol and lipoprotein lipase. A positive correlation was found after the interruption between the lipoprotein lipase activity and the HDL cholesterol concentration. This correlation did not exist before the break in the drug treatment. On the basis of these results the effects of sotalol on lipoprotein metabolism do not seem to be mediated by lipoprotein lipase.

Rats were fed cholesterol, cacao butter, or olive oil diets to determine the effect of dietary lipids on the rate of drug biotransformation in the liver and duodenum. The cholesterol rich diet maintained the hepatic aryl hydrocarbon hydroxylase activity at the same level as did the standard diet. Rats fed olive oil and cacao butter diets showed lower hepatic aryl hydrocarbon hydrorylase activity. The p-nitroanisole O-demethylase activity was doubled in hepatic microsomes of rats fed the high cholesterol diet when compared to rats fed the standard diet. The hepatic uridine diphosphate glucuronosyltransferase activity showed different patterns depending on the in vitro treatment of the microsomal membranes. If the enzyme activity was assayed from the native, untreated microsomes, an increase in the measurable uridine diphosphate glucuronosyl transferase activity was found in rats having cholesterol rich diet. After the in vitro activation of membrane-bound uridine diphosphate glucuronosyltransferase by trypsin, the increase in measurable activity was 10 fold in the group fed the standard diet, 6 fold in group fed cholesterol, 4 fold in group fed cacao butter, and 3 fold in group fed olive oil. Trypsin digestion of microsomes increased the measurable uridine diphosphate glucuronosyltransferase activity less in rats fed diets rich in neutral fats than those fed the standard diet. In the duodenal mucosa, lipid diets decreased the activities of drug hydroxylation and glucuronidation.

1 The effect on plasma lipids of pindolol given orally over a 6 month period to 20 patients with essential hypertension was studied. 2 During therapy an adipose tissue biopsy was taken from nine patients for the determination of lipoprotein lipase (LPL) activity and serum samples were taken for lecithin cholesterol acyltransferase (LCAT) assays. An additional biopsy and serum samples were taken after a 3 weeks' break in pindolol treatment. 3 Plasma free fatty acid and triglyceride concentrations remained similar during treatment. 4 Plasma total cholesterol was slightly lower (P less than 0.05) at 6 months than at 1 month. 5 HDL cholesterol concentration and the ratio of HDL to total cholesterol increased slightly, and the increase of HDL-cholesterol was significant (P less than 0.05) at 1 month. 6 LCAT activity was significantly higher (P less than 0.01) during pindolol treatment than after the break in it. No significant changes in adipose tissue LPL activities were found before and after the break of treatment.

Serum lipid levels were followed in myocardial infarction patients for one year after the infarction and related to their drug use and physical performance. Serum triglyceride concentrations were significantly elevated in patients using diuretics or diuretics and beta-blockers together both 3 and 12 months after the infarction when compared to patients not having drugs. The beta-blockers alone did not change triglycerides. No differences were found in total cholesterol concentration between any of the drug groups. The HDL cholesterol levels were significantly lower in all the drug groups 12 months after the infarction in comparison with the group using no drugs, but 3 months after the infarction these differences were not present. Total work in the exercise stress test correlated negatively with serum triglycerides and total cholesterol and positively with HDL/total cholesterol ratio in the group using no drugs 12 months after the infarction. In beta-blocker users, total work correlated negatively with triglyceride and total cholesterol concentrations. In all drug groups no correlation between total work and HDL/total cholesterol ratio could be found. These data suggest that despite differences in the physical working capacity between the groups, the drugs themselves are major determinants of differences in serum lipids.

Rats were fed for four weeks with different lipid diets to determine the effects on the endoplasmic reticulum membranes of the liver and on the postmitochondrial supernatant fraction of the gastroduodenal mucosa. The diets contained cholesterol, cacao butter, olive oil, and these in combination. The results showed that dietary lipids were able to modify the composition of the hepatic endoplasmic reticulum and, to a lesser extent, that of postmitochondrial fraction of gastroduodenal mucosa. Cacao butter in the diet decreased the relative proportion of protein in hepatic microsomes. Cholesterol and olive oil were able to increase the cholesterol content of microsomes. The trypsin digestion of membranes revealed that cholesterol increased the solubility of microsomal protein and decreased the trypsin sensitive protein-lipid binding. The neutral fat diets increased the binding of proteins to the membrane, and cholesterol had no effect when it was given in combination. The low power photomicrographs revealed vacuolization of the cytoplasm of the hepatocytes when rats were fed on lipid rich diets. Also fatty degeneration was present. Cholesterol in combination with olive oil, however, did normalize the structure of the hepatocytes to a marked extent.

The effect of high dose medroxyprogesterone acetate (MPA) on serum lipids, on adipose tissue lipoprotein lipase (LPL) and serum lecithin cholesterol acyltransferase activities were studied in 15 postmenopausal patients with endometrial cancer. After 2 weeks of MPA treatment total cholesterol decreased by 14% (P less than 0.001) and HDL cholesterol by 33% (P less than 0.01) from the respective pretreatment values; correspondingly the ratio of HDL to total cholesterol decreased (P less than 0.05). The decrease of HDL2 cholesterol was 35% (P less than 0.01) and that of HDL3 cholesterol 15% (P less than 0.01). The levels of serum triglycerides decreased significantly (P less than 0.05) during the treatment period. Serum LCAT activity was significantly lower (P less than 0.05) after treatment than before, but adipose tissue LPL activity was not altered. The mean serum testosterone level decreased significantly (P less than 0.001) from the pretreatment values. Significant positive correlations were present between LPL activity and MPA concentrations and between LPL activity and testosterone concentrations after the drug treatment.