Parenteral administration of iron nitrilotriacetate (FeNTA) to rats resulted in marked loss in body weight, and increases in liver/ and kidney/body weight ratios. Fatalities, due to renal failure, depended on dosage and age of the animals, and were greater (70%) after a single large dose (12 mg iron) than after repeated smaller doses (30%). FeNTA administered subchronically gave rise to an increase in ethane exhalation, and to decreased liver glutathione peroxidase activity, and decreased cytochrome P -450 concentration and benzphetamine N -demethylase activity. It also resulted in severe renal tubular necrosis, with deposition of iron in the tubular cells and loss of brush border alkaline phosphatase activity, resulting in a dose-dependent diuresis, with increased urinary excretion of glucose, iron and lipid peroxidation products, and decreased urine creatinine concentration. NTA alone had none of these effects but slightly decreased the hepatic concentration of iron.

The short-term effects of citral on the liver have been studied in two strains of rat. Hepatomegaly was accompanied in citral-treated rats by an altered distribution of lipid and glycogen in the liver and peroxisome proliferation occurred in a manner reminiscent of that associated with some hypolipidaemic compounds. Specific biochemical markers supported the morphological changes in the peroxisomes. Cyanide-insensitive palmitoyl CoA oxidation showed, at the maximum, fourfold and threefold inductions in Wistar albino and Long Evans hooded rats, respectively. In addition, induction of cytochrome P-450 levels was greater in the Long Evans than in the Wistar rats, the maximal increases recorded being 81 and 27% respectively. A peroxisome-associated polypeptide of molecular weight 80,000 daltons (PPA-80) was induced, especially in Long Evans rats. No alterations in plasma triglycerides or total cholesterol were detected. The differential induction of the mixed-function oxidase system and the differential proliferation of peroxisomes in these two strains of rat suggest that citral may be metabolized differently in the two strains. The study indicates that peroxisomal and possibly also mitochondrial changes are involved in the action of citral on lipid metabolism.

Groups of male Wistar albino rats were administered diets containing sufficient fenofibrate to ensure intakes of either 200, 60 or 13 mg/kg/day or sufficient clofibrate to ensure an intake of 400 mg/kg/day. Four rats from each experimental group and 6 control rats were killed, 3, 7, 14 and 28 days, 8, 12 and 20 weeks and 6, 9, 12 and 18 months after commencement of treatment. At all time points livers were subjected to histological, electron microscopic and biochemical examination, the other major abdominal organs were removed for histological examination. A more extensive necropsy was carried out on rats killed after 12 and 18 months. The major alterations were observed in the liver, although there were also morphological changes in the thyroid, pancreas and kidney after prolonged treatment. The hepatic changes followed a distinct time course. Within 24 h of offering diets containing the compounds to the rats there was accumulation of small droplets of lipid, induction of peroxisomal enzymes and of the specific cytochrome P-450 catalysing ω-hydroxylation of fatty acids and an increase in the number of mitotic figures. More slowly developing changes were loss from the centrilobular zone of fat, glycogen and of glucose 6-phosphatase activity. Here maximal changes were observed after 14 days of treatment. A still more slowly developing change was accumulation of enlarged lipid-loaded lysosomes, which was maximal at 26 weeks, accompanied by the development of lipofuscin bodies. Finally, in animals treated for 12 months or more there was evidence for increasing cell turnover as indicated by an increased number of mitotic figures, more dark cells and induction of serum alanine transaminase. The last 2 groups of changes were not observed in rats treated with 13 mg/kg/day of fenofibrate. In general the degree of change in rats treated with 400 mg/kg/day of clofibrate was similar to those found in rats treated with 60 mg/kg/day of fenofibrate.

Conference Article| February 01 1985 Does lipid accumulation in rodent liver necessarily lead to peroxisome proliferation? SHIRLEY C. PRICE; SHIRLEY C. PRICE *Robens Institute of Industrial and Environmental Health and Safety, Guildford GU2 5XH. Surrey, U.K. Search for other works by this author on: This Site PubMed Google Scholar DEREK E. HALL; DEREK E. HALL †Department of Biochemistry, University of Surrey, Guildford GU2 5XH. Surrey, U.K. Search for other works by this author on: This Site PubMed Google Scholar RICHARD H. HINTON RICHARD H. HINTON *Robens Institute of Industrial and Environmental Health and Safety, Guildford GU2 5XH. Surrey, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1985) 13 (1): 153–155. https://doi.org/10.1042/bst0130153 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation SHIRLEY C. PRICE, DEREK E. HALL, RICHARD H. HINTON; Does lipid accumulation in rodent liver necessarily lead to peroxisome proliferation?. Biochem Soc Trans 1 February 1985; 13 (1): 153–155. doi: https://doi.org/10.1042/bst0130153 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1985 Biochemical Society1985 Article PDF first page preview Close Modal You do not currently have access to this content.

Treatment of rats with 25 mg/kg/day of the neuroleptic drug chlorpromazine for periods of 7, 28 or 90 days causes a slow accumulation of lipid in large droplets in centrilobular hepatocytes. There is little or no damage to hepatocytes as assessed by changes in glucose-6-phosphatase activity and by electron microscopy. Furthermore there is no indication of a change in peroxisomal β-oxidation of fatty acids or in microsomal ω-oxidation of fatty acids. It is, therefore, clear that lipid accumulation in the liver does not automatically induce peroxisomal and microsomal fatty acid oxidising enzymes.

1 Treatment of rats with hypolipidaemic drugs or with the plasticizer di-2-ethyl hexyl phthalate caused significant alterations in the concentration of certain plasma proteins. 2 Certain proteins showed dose-dependent increases, in other cases the plasma concentrations fell in treated animals. 3 The changes were quite distinct from the changes in plasma proteins which occur during the acute-phase response to inflammatory agents. 4 Some changes appeared specific to agents which produce peroxisome proliferation in liver, other alterations appeared associated with mild, but sustained, liver injury.

The protective effect of the sulphur-containing amino acids N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity was evaluated in the hamster by biochemical and histological methods. Of the animals receiving paracetamol alone 25% died within 24 h following administration. All surviving animals showed acute hepatocellular injury and marked loss of cytochrome P-450 and hepatic mixed-function oxidase activities. Simultaneous administration of N-acetylcysteine decreased the mortality rate, partly prevented the paracetamol-induced liver damage and partly restored enzyme activities. Simultaneous administration of S-carboxymethylcysteine with paracetamol afforded no protection. Kidneys from all animals were histologically normal. Human liver microsomes and liver microsomes from 3-methylcholanthrene-pretreated hamsters metabolished paracetamol to intermediate(s) that bind covalently to microsomal proteins. The rate of covalent binding was inhibited markedly by N-acetylcysteine and to a lesser extent by S-carboxylmethylcysteine.

It has frequently been suggested that the jaundice which occurs in a small percentage of human patients following treatment with chlorpromazine is due to a hypersensitivity reaction. It has, however, proved impossible to obtain an animal model for this condition. We now show that oral administration of chlorpromazine at 25 mg/kg per day to Wistar albino rats results in formation of both humoral and secretory antibodies to chlorpromazine. We also demonstrate that the severity of the hepatic changes observed in chlorpromazine-fed animals (periportal glycogen loss and centrilobular fatty change) is enhanced by preimmunization of the rats via the gut-associated lymphoid tissue with a chlorpramizine-protein conjugate. There was, however, no correlation between the titre of either serum or biliary antibodies in individual animals and the degree of liver damage. Our results therefore suggest than an immune mechanism is indeed implicated in chlorpromazine toxicity but show clearly that toxic symptoms are not a simple consequence of the formation of anti-chlorpromazine antibodies.

Conference Article| August 01 1982 Accumulation of lipid-rich lysosomes in the livers and kidneys of animals treated with hypolipidaemic agents SHIRLEY C. PRICE; SHIRLEY C. PRICE *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar RICHARD H. HINTON; RICHARD H. HINTON *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar DEREK E. HALL; DEREK E. HALL †Department of Biochemistry, University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar PAUL GRASSO; PAUL GRASSO †Group Occupational Health Centre, BP Research Centre, Sunbury, Middx., U.K. Search for other works by this author on: This Site PubMed Google Scholar JAMES W. BRIDGES JAMES W. BRIDGES *Robens Institute of Industrial and Environmental Health, Safety and University of Surrey, Guildford, Surrey GU2 5XH, U.K. Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1982 Biochemical Society1982 Biochem Soc Trans (1982) 10 (4): 244. https://doi.org/10.1042/bst0100244 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation SHIRLEY C. PRICE, RICHARD H. HINTON, DEREK E. HALL, PAUL GRASSO, JAMES W. BRIDGES; Accumulation of lipid-rich lysosomes in the livers and kidneys of animals treated with hypolipidaemic agents. Biochem Soc Trans 1 August 1982; 10 (4): 244. doi: https://doi.org/10.1042/bst0100244 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1982 Biochemical Society1982 Article PDF first page preview Close Modal You do not currently have access to this content.