Coenzyme Q in pregnant women and rats with intrahepatic cholestasis
Manuela R. Martinefski
Analytical Chemistry, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Both authors contributed equally to the study.Search for more papers by this authorMario D. Contin
Analytical Chemistry, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Both authors contributed equally to the study.Search for more papers by this authorMyrian R. Rodriguez
Pathophysiology-INIGEM, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorEstefanía M. Geréz
Physical Chemistry-IBIMOL, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Search for more papers by this authorMónica L. Galleano
Physical Chemistry-IBIMOL, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorSilvia E. Lucangioli
Drug Quality, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorLiliana G. Bianciotti
Pathophysiology-INIGEM, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorCorresponding Author
Valeria P. Tripodi
Drug Quality, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Correspondence
Professor Dr Valeria P. Tripodi, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Junin 956, 5th floor, Buenos Aires 1113, Argentina
Tel/Fax: +54 11 4964 8200 (int. 8267)
e-mail: [email protected]
Search for more papers by this authorManuela R. Martinefski
Analytical Chemistry, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Both authors contributed equally to the study.Search for more papers by this authorMario D. Contin
Analytical Chemistry, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Both authors contributed equally to the study.Search for more papers by this authorMyrian R. Rodriguez
Pathophysiology-INIGEM, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorEstefanía M. Geréz
Physical Chemistry-IBIMOL, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Search for more papers by this authorMónica L. Galleano
Physical Chemistry-IBIMOL, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorSilvia E. Lucangioli
Drug Quality, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorLiliana G. Bianciotti
Pathophysiology-INIGEM, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Search for more papers by this authorCorresponding Author
Valeria P. Tripodi
Drug Quality, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Buenos Aires, Argentina
Consejo Nacional de Investigaciones Científicas y Tecnológicas, CONICET, Buenos Aires, Argentina
Correspondence
Professor Dr Valeria P. Tripodi, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Junin 956, 5th floor, Buenos Aires 1113, Argentina
Tel/Fax: +54 11 4964 8200 (int. 8267)
e-mail: [email protected]
Search for more papers by this authorAbstract
Background & Aims
Intrahepatic cholestasis of pregnancy is a high-risk liver disease given the eventual deleterious consequences that may occur in the foetus. It is accepted that the abnormal accumulation of hydrophobic bile acids in maternal serum are responsible for the disease development. Hydrophobic bile acids induce oxidative stress and apoptosis leading to the damage of the hepatic parenchyma and eventually extrahepatic tissues. As coenzyme Q (CoQ) is considered an early marker of oxidative stress in this study, we sought to assess CoQ levels, bile acid profile and oxidative stress status in intrahepatic cholestasis.
Methods
CoQ, vitamin E and malondialdehyde were measured in plasma and/or tissues by HPLC-UV method whereas serum bile acids by capillary electrophoresis in rats with ethinyl estradiol-induced cholestasis and women with pregnancy cholestasis.
Results
CoQ and vitamin E plasma levels were diminished in both rats and women with intrahepatic cholestasis. Furthermore, reduced CoQ was also found in muscle and brain of cholestatic rats but no changes were observed in heart or liver. In addition, a positive correlation between CoQ and ursodeoxycholic/lithocholic acid ratio was found in intrahepatic cholestasis suggesting that increased plasma lithocholic acid may be intimately related to CoQ depletion in blood and tissues.
Conclusion
Significant CoQ and vitamin E depletion occur in both animals and humans with intrahepatic cholestasis likely as the result of increased hydrophobic bile acids known to produce significant oxidative stress. Present findings further suggest that antioxidant supplementation complementary to traditional treatment may improve cholestasis outcome.
References
- 1Germain AM, Carvajal JA, Glasinovic JC, Kato S, Williamson C. Intrahepatic cholestasis of pregnancy: an intriguing pregnancy-specific disorder. J Soc Gynecol Investig 2002; 9: 10–4.
- 2Reid R, Ivey KJ, Recoret RH, Storey B. Fetal complications of obstetric cholestasis. BMJ 1976; 1: 870–2.
- 3Lammert F, Ulrich Marschall H, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000; 33: 1012–21.
- 4Glantz A, Ulrich Marschall H, Mattson L. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–74.
- 5Monte MJ, Marin JJ, Antelo A, Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15: 804–16.
- 6Barshop B, Gangoit J. Analysis of coenzyme Q10 in human blood and tissues. Mitochondrion 2007; 7: 89–93.
- 7Crane FL. Biochemical functions of coenzyme Q10. J Am Coll Nutr 2001; 20: 591–8.
- 8Stocker R, Bowry WV, Frei B. Ubiquinol-10 protects human low density lipoproteins more efficiently against lipid peroxidation than does α-tocopherol. Proc Natl Acad Sci USA 1991; 88: 1646–50.
- 9Compagnoni G, Lista G, Giuffrè B, Mosca F, Marini A. Coenzyme Q10 levels in maternal plasma and cord blood: correlations with mode of delivery. Biol Neonate 2004; 86: 104–7.
- 10Miles MV, Tang PH, Liles L, et al. Validation and application of an HPLC-EC method for analysis of coenzyme Q10 in blood platelets. Biomed Chromatogr 2008; 22: 1403–8.
- 11Quinzii C, Naini A, Salviati L, et al. A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am J Hum Genet 2006; 78: 345–9.
- 12Rötig A, Mollet J, Rio M, Munnich A. Infantile and pediatric quinone deficiency diseases. Mitochondrion 2007; 7(Suppl): S112–21.
- 13Cooper JM, Korlipara LV, Hart PE, Bradley JL, Schapira AH. Coenzyme Q10 and vitamin E deficiency in Friedreich's ataxia: predictor of efficacy of vitamin E and coenzyme Q10 therapy. Eur J Neurol 2008; 15: 1371–9.
- 14Molineux S, Young J, Florkowshi C, Lever M. Coenzyme Q10: is there a clinical role and a case for measurement? Clin Bioche Rev 2008; 29: 71–8.
- 15Cobanoglu U, Demir H, Cebi A, et al. Lipid peroxidation, DNA damage and coenzyme Q10 in lung cancer patients–markers for risk assessment? Asian Pac J Cancer Prev 2011; 12: 1399–403.
- 16Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: an update. Nutrition 2010; 26: 250–4.
- 17Miles MV, Putnam PE, Miles L, et al. Acquired coenzyme Q10 deficiency in children with recurrent food intolerance and allergies. Mitochondrion 2011; 11: 127–35.
- 18Rodríguez Garay E. Cholestasis: human disease and experimental animal models. Ann Hepatol 2003; 2: 150–8.
- 19Trauner M. Molecular alterations of canalicular transport systems in experimental models of cholestasis: possible functional correlations. Yale J Biol Med 1997; 70: 365–78.
- 20Tang PH, Miles MV, Miles L, et al. Measurement of reduced and oxidized coenzyme Q9 and coenzyme Q10 levels in mouse tissues by HPLC with coulometric detection. Clin Chim Acta 2004; 341: 173–84.
- 21Contin M, Lucangioli S, Martinefski M, Flor S, Tripodi V. Miniaturized HPLC-UV method for analysis of coenzyme Q10 in human plasma. J Liq Chrom Relat Tech 2011; 34: 2485–94.
- 22Contin M, Martinefski M, Lucangioli S, Tripodi V. Sistema cromatográfico miniaturizado para la determinación de coenzima Q10 en plasma, músculo y plaquetas. Acta Bioquím Clín latinoam 2011; 45: 273–8.
- 23Khan A, Khan MI, Iqbal Z, et al. An optimized and validated RP-HPLC/UV detection method for simultaneous determination of all-trans-retinol (vitamin A) and alpha-tocopherol (vitamin E) in human serum: comparison of different particulate reversed-phase HPLC columns. J Chromatog B Analyt Technol Biomed Life Sci 2010; 878: 2339–47.
- 24Templar J, Kon SP, Milligan TP, Newman DJ, Raftery MJ. Increased plasma malondialdehyde levels in glomerular disease as determined by a fully validated HPLC method. Nephrol Dial Transplant 1999; 14: 946–51.
- 25Tripodi V, Lucangioli S, Scioscia S, Carducci C. Simultaneous determination of free and conjugated bile acids in serum by cyclodextrin-modified micellar electrokinetic chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2003; 785: 147–55.
- 26Miles MV, Putnam PE, Miles L, et al. Effects of coenzyme Q10 administration on its tissue concentrations, mitochondrial oxidant generation, and oxidative stress in the rat. Free Radic Biol Med 2002; 33: 627–38.
- 27Castaño G, Lucangioli S, Sookoian S, et al. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy. Clin Sci 2006; 110: 459–65.
- 28Billington D, Evans CE, Godfrey PP, Coleman R. Effects of bile salts in the plasma membranes of isolated rat hepatocytes. Biochem J 1980; 188: 321–7.
- 29Sokol RJ, Straka MS, Dahl R, et al. Role of oxidant stress in the permeability transition induced in rat hepatic mitochondria by hydrophobic bile acids. Pediatr Res 2001; 49: 519–31.
- 30Ljubundic P, Fuhrman B, Oiknine J, Aviram M, Bomzon A. Effect of deoxycholic acid and ursodeoxycholic acid on lipid peroxidation in cultured macrophages. Gut 1996; 39: 475–8.
- 31Attili AF, Angelico M, Cantafora A, Alvaro D, Capocaccia L. Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 1986; 19: 57–69.
- 32Roda A, Minutello A, Angellotti MA, Fini A. Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octano/water partition coefficient and reverse phase HPLC. J Lipid Res 1990; 31: 1433–43.
- 33Perez MJ, Macias RI, Duran C, et al. Oxidative stress and apoptosis in fetal rat liver induced by maternal cholestasis. Protective effect of ursodeoxycholic acid. J Hepatol 2005; 43: 324–32.
- 34Perez MJ, Macias RI, Marin J. Maternal cholestasis induces placental oxidative stress and apoptosis. Protective effect of ursodeoxycholic acid. Placenta 2006; 27: 34–41.
- 35Perez MJ, Castaño B, Jimenez S, et al. Maternal ethanol consumption during pregnancy enhances bile acid-induced oxidative stress and apoptosis in fetal rat liver. Toxicology 2006; 225: 183–94.
- 36Crocenzi FA, Pellegrino JM, Catania VA, et al. Galactosamine prevents ethinylestradiol-induced cholestasis. Drug Metab Dispos 2006; 34(6): 993–7.
- 37Henríquez-Hernández LA, Flores-Morales A, Santana-Farré R, et al. Role of pituitary hormones on 17alpha-ethinylestradiol-induced cholestasis in rat. J Pharmacol Exp Ther 2007; 320(2): 695–705.
- 38Gumuccio JJ, Valdivieso VD. Studies on the mechanism of the ethynylestradiol impairment of bile flow and bile salt excretion in the rat. Gastroenterology 1971; 61: 339–44.
- 39Aboutwerat A, Pemberton PW, Smith A, et al. Oxidant stress is a significant feature of primary biliary cirrhosis. Biochim Biophys Acta 2003; 1637: 142–50.
- 40Morio LA, Leone A, Sawant SP, et al. Hepatic expression of heme oxygenase-1 and antioxidant response element-mediated genes following administration of ethinyl estradiol to rats. Toxicol Appl Pharmacol 2006; 216: 416–25.
- 41Roma MG, Sanchez Pozzi EJ. Oxidative stress: a radical way to stop making bile. Ann Hepatol 2008; 7: 16–33.
- 42Copple BL, Jaeschke H, Klaassen CD. Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 2010; 30: 195–204.
- 43Jaeschke H. Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 2011; 26: 173–9.
- 44Dueland S, Reichen J, Everson GT, Davis RA. Regulation of cholesterol and bile acid homeostasis in bile-obstructed rats. Biochem J 1991; 280: 373–7.
- 45Heuman DM, Hernandez CR, Hylemon PB, et al. Regulation of bile acid synthesis. I. Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat. Hepatology 1988; 8: 358–65.
- 46Erickson SK, Jaeckle S, Lear SR, Brady SM, Havel RJ. Regulation of hepatic cholesterol and lipoprotein metabolism in ethinyl estradiol-treated rats. J Lipid Res 1989; 30: 1763–71.
- 47Shefer S, Nguyen L, Salen G, et al. Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate. J Clin Invest 1990; 85: 1191–8.
- 48Jauniaux E, Watson AL, Hempstock J, et al. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am J Pathol 2000; 157: 2111–22.
- 49Saugstad OD. Oxidative stress in the newborn – a 30-year perspective. Biol Neonate 2005; 88: 228–36.
- 50Noia G, Littarru GP, De Santis M, et al. Coenzyme Q10 in pregnancy. Fetal Diagn Ther 1996; 11: 264–70.
- 51Floreani A, Baragiotta A, Martines D, et al. Plasma antioxidant levels in chronic cholestatic liver diseases. Aliment Pharmacol Ther 2000; 14: 353–8.
- 52Lucangioli S, Castaño G, Contin M, Tripodi V. Lithocholic acid as a biomarker of intrahepatic cholestasis of pregnancy during ursodeoxycholic acid treatment. Ann Clin Biochem 2009; 46: 44–9.