Download PDF
Horm Metab Res 2014; 46(11): 782-788
DOI: 10.1055/s-0034-1384605
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Sex-Dependent Metabolic Alterations of Rat Liver After 12-Week Exposition to Haloperidol or Clozapine

M. von Wilmsdorff
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
M.-L. Bouvier
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
U. Henning
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
,
A. Schmitt
2   Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich, München, Germany
3   Laboratory of Neuroscience (LIM27), Institute of Psychiatry, University of Sao Paulo, São Paulo – SP, Brazil
,
T. Schneider-Axmann
2   Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich, München, Germany
,
W. Gaebel
1   Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received 27 January 2014

accepted 01 July 2014

Publication Date:
08 August 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Antipsychotic drugs are known to have sex-dependent effects on metabolic homeostasis. Liver plays a crucial role in drug degradation as well as in glucose and lipid metabolism. The present study examines the influence of clozapine and haloperidol on metabolic liver parameters. Over 12 weeks, male and female Sprague-Dawley rats were fed ground pellets containing clozapine or haloperidol. Liver mass was weighed and liver index calculated. Liver transaminases (ALAT, ALP), malondialdehyde, glucose, triglycerides, total cholesterol, HDL-cholesterol, and glycogen were determined. Finally, SREBP-1 and SREBP-2 as well as neutral fat deposits were examined. In male rats fed with clozapine, we found increased liver mass correlated with an increased liver index, high triglyceride levels, a high ratio of SREBP-1, and an elevated neutral fat distribution. Male and female haloperidol treated rats showed decreased liver mass and increased neutral fat deposition. Malondialdehyde was increased in all rats receiving antipsychotic medication indicating elevated oxidative stress. In both male and female clozapine treated rats, we found glycogen depletion related to decreased glucose levels in females. While liver transaminases were unchanged in the clozapine group, ALAT was elevated after haloperidol treatment in both sexes. Chronic clozapine intake exerts sex-dependent effects on hepatic metabolism. Although haloperidol has been shown to change fewer metabolic parameters, it causes oxidative stress and neutral fat deposits in liver tissue in both sexes.

Key words

glucose - glycogen - lipid metabolism - oxidative stress

Supporting Information

 

  • References

  • 1 Manu P, Sarpal D, Muir O, Kane JM, Correll CU. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res 2011; 134: 180-186
    PubMedGoogle Scholar
  • 2 Bai YM, Lin CC, Chen JY, Chen TT, Su TP, Chou P. Association of weight gain and metabolic syndrome in patients taking clozapine: An 8-year cohort study. J Clin Psychiatry 2011; 72: 751-756
    CrossrefPubMedGoogle Scholar
  • 3 Grover S, Nebhinani N, Chakrabarti S, Avasthi A, Kulhara P. Metabolic syndrome among patients receiving clozapine: A preliminary estimate. Indian J Pharmacol 2011; 43: 591-595
    CrossrefPubMedGoogle Scholar
  • 4 Miljevic C, Nikolic M, Nikolic-Kokic A, Jones DR, Niketic V, Lecic-Tosevski D, Spasic MB. Lipid status, and anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 303-307
    CrossrefPubMedGoogle Scholar
  • 5 De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol 2011; 8: 114-126
    CrossrefPubMedGoogle Scholar
  • 6 Krakowski M, Czobor O, Cirome L. Weight gain, metabolic parameters, and the impact of race in aggressive inpatients randomized to double-blind clozapine, olanzapine or haloperidol. Schizophr Res 2009; 110: 95-102
    CrossrefPubMedGoogle Scholar
  • 7 von Wilmsdorff M, Bouvier M-L, Henning U, Schmitt A, Schneider-Axmann T, Gaebel W. The sex-dependent impact of chronic clozapine and haloperidol treatment on characteristics of the metabolic syndrome in a rat model. Pharmacopsychiatry 2012; 46: 1-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Fernø J, Vik-Mo AO, Jassim G, Håvik B, Berge K, Skrede S, Gudbrandsen OA, Waage J, Lunder N, Mørk S, Berge RK, Jørgensen HA, Steen VM. Acute clozapine exposure in vivo induces lipid accumulation and marked sequential changes in the expression of SREBP, PPAR, and LXR target genes in rat liver. Psychopharmacol 2009; 203: 73-84
    CrossrefPubMedGoogle Scholar
  • 9 Lauressergues E, Staels B, Valeille K, Majd Z, Hum DW, Duriez P, Cassac D. Antipsychotic drug action on SREBPs-related lipogenesis and cholesterogenesis in primary rat hepatocytes. Naunyn-Schmied Arch Pharmacol 2010; 381: 427-439
    PubMedGoogle Scholar
  • 10 Smith GC, Chaussade C, Vickers M, Jensen J. Atypical antipsychotic drugs induce derangements in glucose homeostasis by acutely increasing glucagon secretion and hepatic glucose output in the rat. Diabetologica 2008; 51: 2309-2317
    CrossrefPubMedGoogle Scholar
  • 11 Smith GC, Vickers MH, Cognard E, Shepherd PR. Clozapine and quetiapine acutely reduce glucgon-like-peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behavior. Schizophr Res 2009; 115: 30-40
    CrossrefPubMedGoogle Scholar
  • 12 Jassim G, Skrede S, Vázques MJ, Wegedal H, Vik-Mo AO, Lunder N, Diéguez C, Vidal-Puig A, Berge RK, López M, Steen VM, Fernø J. Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat. Psychopharmacology 2011; 219: 783-794
    PubMedGoogle Scholar
  • 13 Raeder MB, Fernø J, Vik-Mo AO, Steen VM. SREBP activation by antipsychotic- and antidepressant-drugs in cultured human liver cells: relevance for metabolic side-effects?. Mol Cell Biochem 2006; 289: 167-173
    CrossrefPubMedGoogle Scholar
  • 14 Fernø J, Skrede S, Vik-Mo AO, Håvik B, Steen VM. Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines: Marked differences between various antipsychotic drugs. BMC Neurosci 2006; 7: 69-70
    CrossrefPubMedGoogle Scholar
  • 15 Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 1125-1131
    CrossrefPubMedGoogle Scholar
  • 16 Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S, Siu C. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res 2009; 110: 103-110
    CrossrefPubMedGoogle Scholar
  • 17 Vidarsdottir S, de Leeuw van Weenen JE, Fröhlich M, Roelfsema F, Romijn JA, Pijl H. Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab 2010; 95: 119-125
    PubMedGoogle Scholar
  • 18 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analyt Biochem 1979; 95: 351-358
    CrossrefPubMedGoogle Scholar
  • 19 Xu P, Zhang X, Li Y, Yu C, Xu L, Xu G. Research on the protection of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats. JZUS Science B 2006; 7: 627-633
    PubMedGoogle Scholar
  • 20 Dalla Libera A, Scutari G, Boscolo R, Rigobello MP, Bindoli A. Antioxidant properties of clozapine and related neuroleptics. Free Radic Res 1998; 29: 151-157
    CrossrefPubMedGoogle Scholar
  • 21 Magliaro BC, Saldanha CJ. Clozapine protects PC-12 cells from death due to oxidative stress induced by hydrogen peroxide via a cell-type specific mechanism involving inhibition of extracellular signal-regulated kinase phosphorylation. Brain Res 2009; 1283: 14-24
    CrossrefPubMedGoogle Scholar
  • 22 Kropp S, Kern V, Lange K, Degner D, Hajak G, Kornhuber J, Rüther E, Emrich HM, Schneider U, Bleich S. Oxidative stress during treatment with first- and second-generation antipsychotics. J Neuropsychiatry Clin Neurosci 2005; 17: 227-231
    CrossrefPubMedGoogle Scholar
  • 23 Walss-Bass C, Weintraub ST, Hatch J, Mintz J, Chaudhuri AR. Clozapine causes oxidation of proteins involved in energy metabolism: a possible mechanism for antipsychotic-induced metabolic alterations. Int J Neuropsychopharmacol 2008; 11: 1097-1104
    CrossrefPubMedGoogle Scholar
  • 24 Baig MR, Navaira E, Escamilla MA, Raventos H, Walss-Bass C. Clozapine treatment causes oxidation of proteins involved in energy metabolism in lymphoblastoid cells: a possible mechanism for antipsychotic-induced metabolic alterations. J Psychiatr Pract 2010; 16: 325-333
    CrossrefPubMedGoogle Scholar
  • 25 Gama CS, Salvador M, Andreazza AC, Kapezinski F, Belmonte-de-Abreu PS. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: A study of patients treated with haloperidol or clozapine. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 512-515
    CrossrefPubMedGoogle Scholar
  • 26 Zhang XY, Tan YL, Cao LY, Wu GY, Xu Q, Shen Y, Zhou DF. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res 2006; 81: 291-300
    CrossrefPubMedGoogle Scholar
  • 27 Singh OP, Chakraborty I, Dasgupta A, Datta S. A comparative study of oxidative stress and interrelationship of important antioxidants in haloperidol and olanzapine treated patients suffering from schizophrenia. Indian J Psychiatry 2008; 50: 171-176
    CrossrefPubMedGoogle Scholar
  • 28 Halici Z, Dursun H, Keles ON, Odaci E, Suleyman H, Aydin N, Cadirci E, Kalkan Y, Unal B. Effect of chronic treatment of haloperidol on the rat liver; a stereological and histopathological study. Naunyn-Schmied Arch Pharmacol 2009; 379: 253-261
    PubMedGoogle Scholar
  • 29 Wei Z, Mousseau DD, Dai Y, Cao X, Li XM. Haloeridol induces apoptosis via the sigma2receptor system and Bcl-XS. J Pharmacogenetics 2006; 6: 279-288
    PubMedGoogle Scholar
  • 30 Mouradian-Stamatiadis L, Dumortier G, Januel D, Delmas BA, Cabaret W. Liver function tests during treatment with antipsychotic drugs: a case series of 23 patients. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1409-1411
    CrossrefPubMedGoogle Scholar
  • 31 Gaertner I, Altendorf K, Batra A, Gaertner HJ. Relevance of liver enzyme elevations with four different neuroleptics: a retrospective review of 7263 treatment courses. J Clin Psychopharmacol 2001; 21: 215-222
    CrossrefPubMedGoogle Scholar
  • 32 Amacher DE, Schomaker SJ, Burkhardt JE. The relationship among microsomal enzyme induction, liver weight and histological change in rat toxicology studies. Food Chem Tox 1998; 36: 831-839
    CrossrefPubMedGoogle Scholar
  • 33 Nadal-Casellas A, Proenza AM, Lladó I, Gianotti M. Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity. Biochem Cell Biol 2012; 90: 164-172
    CrossrefPubMedGoogle Scholar
  • 34 Riant E, Waget A, Cogo H, Amal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat induced insulin resistance and glucose intolerance in mice. Endocrinology 2009; 150: 2109-2117
    CrossrefPubMedGoogle Scholar
  • 35 Knebel B, Haas J, Lehr S, Jacob S, Nitzgen U, Müller-Wieland D, Kotzka J. Mitochondrien und Peroxisomen sind in der Leber von db/db-Mäusen verändert und spielen möglicherweise eine Rolle für die Entwicklung einer Fettleber. Diabetologie Stoffwechsel 2010; 5: 254-258
    PubMedGoogle Scholar
  • 36 Ibrahim SH, Akazawa Y, Cazanave SC, Bronk SF, Elmi NA, Werneburg NW, Billadeau DD, Gores GJ. Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis. J Hepatol 2011; 54: 765-772
    CrossrefPubMedGoogle Scholar
  • 37 Lauressergues E, Bert E, Duriez P, Hum D, Majd Z, Staels B, Cussac D. Does endoplasmic reticulum stress participate in APD-induced hepatic metabolic dysregulation?. Neuropharmacology 2012; 62: 784-796
    CrossrefPubMedGoogle Scholar
  • 38 Infantino V, Iacobazzi V, De Santis F, Mastrapasqua M, Palmieri F. Transcription of the mitochondrial citrate carrier gene: Role of SREBP-1, upregulation by insulin and downregulation by PUFA. Biochem Biophys Res Commun 2007; 356: 249-254
    CrossrefPubMedGoogle Scholar
  • 39 Menga A, Infantino V, Iacobazzi F, Convertini P, Palmieri F, Iacobazzi V. Insight into mechanism of in vitro insulin secretion increase induced by antipsychotic clozapine: role of FOXA1 and mitochondrial citrate carrier. Eur Neuropsychopharmacology 2012; 23: 978-987
    PubMedGoogle Scholar
  • 40 Patel S, Macaulay K, Woodgett JR. Tissue-specific analysis of glycogen synthase kinase-3α (GSK-3α) in glucose metabolism: effect of strain variation. PLOS One 2011; 6: e15845
    CrossrefPubMedGoogle Scholar
  • 41 Sutton LR, Rushlow WJ. The effects of neuropsychiatric drugs on glycogen synthase kinase-3 signaling. Neuroscience 2011; 199: 116-124
    CrossrefPubMedGoogle Scholar
  • 42 Alimohamad H, Rajakumar N, Seah YH, Rushlow W. Antipsychotics alter the protein expression levels of β-catenin and GSK-3 in the rat medial prefrontal cortex and striatum. Biol Psychiatry 2005; 57: 533-542
    CrossrefPubMedGoogle Scholar
  • 43 Chen S, Zhao J, Gao L. Long-term ethanol feeding impairs rats’ liver and influences glycogen and GSK-3, GLUT4 and AMPK. 2011 www.res-medical.com/medicalpaper/14596
    PubMedGoogle Scholar
  • 44 Kokubun E, Hirabara SM, Fiamoncini J, Curi R, Haebisch H. Changes of glycogen content in liver, skeletal muscle, and heart from fasted rats. Cell Biochem Funct 2009; 27: 488-495
    CrossrefPubMedGoogle Scholar