No abstract

Using an initiation--selection--promotion protocol for induction of liver tumors in Wistar rats, the modulating action of various peroxisome proliferators on neoplasia as well as on selected biochemical parameters was studied. After treatment with diethylnitrosamine (DEN), the animals were subsequently subjected to a selection procedure involving feeding of 2-acetylaminofluorene (2-AAF), and in the middle of the 2-AAF treatment, a single necrogenic dose of carbon tetrachloride. Following a recovery period, the rats were fed a diet containing 0.1% nafenopin (NAF), 0.015% perfluorooctanoic acid (PFOA), 0.05% 2,4-dichlorophenoxyacetic acid (2,4-D), 0.05% 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) or 0.05% phenobarbital (PB) as a positive control. When the animals were killed, 7 months after initiation, the incidence of hepatocellular carcinoma was 83, 33 and 16% in the animals treated with NAF, PFOA or 2,4,5-T respectively. No cancers were observed in controls, or in the 2,4,-D groups. In comparison with controls, NAF and PFOA caused a 60-and 24-fold increase inthe peroxisomal beta-oxidation of fatty acids respectively, but only about a 2-fold increase in the catalase activity, 2,4-D and/or 2,4,5-T were much less active in this respect, giving approximately a doubling in the rate of fatty acid oxidation. The specific activity of D-amino acid and glycolate oxidases were significantly depressed, whereas the urate oxidase levels were apparently unaffected by the NAF and PFOA treatment. The results suggest that the selective induction of peroxisomal fatty acid oxidation is consistent with the hypothesis that imbalance between H2O2 overproduction and its destruction could play a role in the modulation of hepatocarcinogenesis by peroxisome proliferators.

Although peroxisome proliferators are considered non-genotoxic agents, most of them, nevertheless, were found to promote and/or induce, hepatocellular carcinoma (HCC) in rodents. The aim of the present study is, first, to investigate whether the peroxisome proliferator perfluorooctanoic acid (PFOA) possesses inherent liver cancer promoting activity, and second, to study the possible mechanisms involved. To acheive these aims two protocols have been applied, a biphasic protocol (initiation by diethyl-nitrozamine (DEN) 200 mg/kg i.p. followed by treatment with 0.005% or 0.02% perflourooctanoic acid (PFOA) for 14 and 25 weeks) and a triphasic initiation, selection-promotion (IS) protocol (initiation by giving 200 mg/kg DEN i.p. followed by a selection procedure for 2 weeks consisting of giving 0.03% 2-acetylaminofluorene (2-AAF) in diet). In the middle of this treatment a single oral dose of carbon tetrachloride (2.0 ml/kg) was given, followed by giving diet containg 0.015% of PFOA for 25 weeks. After applying both protocols, our results showed slight increase in the catalase activity while acyl CoA oxidase activity was markedly increased. Both experiments indicated that PFOA has a liver cancer promoting activity. Other groups of rats were given either basal diet or diet containing 0.02% PFOA. Five or nine weeks later they were sacrificed and the levels of 8-hydroxydeoxyguanosine in the isolated DNA were estimated. The data showed a slight nonetheless insignificant increase in 8-hydroxydeoxyguanosine. From the present data, it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity.

Type 2 of diabetes mellitus (DM) is associated with progressive failure of pancreatic B-cells to secrete insulin, decreased insulin action, due to reduced insulin receptors at the target sites. Dyslipidemia is a common risk of DM and is responsible to a large extent for cardiovascular disease-related morbidity and mortality. This study was planned to compare the effects of metformin alone and a combination of metformin and insulin in presence of simvastatin on glycemic and lipid levels in Libyan diabetic patients. This retrospective study was conducted at Benghazi Diabetic Center (Libya) on 100 patients with type 2 DM of 40-60 years old. Patients were selected for follow up on basis of inclusion and exclusion criteria, and were divided into three groups. The first group (n=30), received metformin (1-2 gm/day). The second group (n=40) received metformin (1-2 gm/day) and insulin (mixtard 30/70, 30-60 units/day) and third group (n=30) received metformin (1-2 gm/day), insulin (30-60 units/day) plus simvastatin (40 mg/day). Glucose blood levels (FBG, PPBG and HBA1c), lipid profile (TC, TG, HDL-C, LDL-C and AI), hepatic function (ALT, AST, ALP and Bilirubin) and renal function (creatinine and urea) were measured for each patient. All the patients had a good glycemic control with significant decrease in HbAc1 of metformin plus insulin treated group. No significant differences in lipid profile of metformin treated group and metformin plus insulin treated group were observed. Date revealed both significant increase in HDL-C and decrease in TC, LDL-C and atherogenic index levels but without any change in TG in metformin and insulin treated group as compared with metformin, insulin plus simvastatin treated group. All the findings of hepatic and renal functions were within the normal range except for bilirubin which significantly increased in metformin, insulin plus simvastatin treated group compared with other treated groups. In conclusion, the efficacy of metformin in controlling hyperglycemia was enhanced with insulin without negative effects. Simvastatin was effective in controlling dyslipidemia associated with DM and produced a profound reduction in TC and LDL-C of the patients.

A group of patients with and hyperlipidemia were divided into male and female groups and further subdivided into 3 groups. These groups received, either simvastatin (20 mg daily), Omega3-fatty acid (2g/day), or both. The blood pressure and lipid profile were measured before and after 4 weeks of treatment. Our data showed that treatment with simvastatin did not produce significant effect on blood pressure, however the blood pressure was significantly reduced in patients received omega 3-fatty acid or simvastatin plus omega3-fatty acid. The total cholesterol (TC), triglycerides (TG), and low density lipoprotein (LDL) significantly decreased in all treated groups. The high density lipoprotein (HDL) significantly increased in all treated groups except in the group of males receiving simvastatin.Alanine transaminase (ALT) increased significantly in female and male groups receiving simvastatin, but significantly decreased in same groups receiving omega 3-fatty acid and in the males receiving simvastatin plus omega3-fatty acid. The aspartate transaminase (AST) levels significantly decreased in all treated groups except in the female group given omega3fatty acid. The alkaline phosphatase (ALP) significantly increased only in the groups given simvastatin alone. The levels of urea and creatinine were not affected in all groups. In our prospective study we found that simvastatin decreased TC, TG and LDL, and resulted in elevation of liver transaminases. Omega3-fatty acid alone or in combination with simvastatin has similar effect on lipid profile and it significantly reduces blood pressure without affecting liver or renal function.