Cofactor Supply as a Rate-Limiting Determinant of Hepatic Conjugation Reactions

  • L. A. Reinke
  • F. C. Kauffmann
  • R. G. Thurman
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 112)


The metabolism of drugs, other xenobiotics, and endogenous compounds by conjugation is usually catalyzed by specific transferases; the notable exceptions are the non-enzymatic conjugation of highly reactive intermediates with glutathione (GSH) and the formation of acyl-linked glucuronides (reviewed in Chaps. 13 and 16 of this volume). Because of the important role of transferases in catalyzing conjugation reactions, these enzymes have been studied extensively, and the properties of the important conjugating enzymes are described in Chaps. 1–7.


Perfuse Liver Inorganic Sulfate Sulfate Conjugation Hepatic Glutathione Buthionine Sulfoximine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aarts EM (1966) Differentiation of the barbiturate stimulation of the glucuronic acid pathway from de novo enzyme synthesis. Biochem Pharmacol 15: 1469–1477PubMedCrossRefGoogle Scholar
  2. Al-Turk W, Reinke LA (1983) Diminished conjugation of products of mixed-function oxidation in perfused livers from hypophysectomized rats. Pharmacology 27: 74–84PubMedCrossRefGoogle Scholar
  3. Angus PW, Mihaly GW, Morgan DJ, Smallwood RA (1987) Hypoxia impairs conjugation and elimination of harmol in the isolated perfused rat liver. J Pharmacol Exp Ther 240: 931–936PubMedGoogle Scholar
  4. Angus PW, Mihaly GW, Morgan DJ, Smallwood RA (1988) Synergistic effects of hypoxia and fasting on harmol elimination in the isolated perfused rat liver. Biochem Pharmacol 37: 1207–1212PubMedCrossRefGoogle Scholar
  5. Aw TY, Jones DP (1982) Secondary bioenergetic hypoxia: inhibition of sulfation and glucuronidation reactions in isolated hepatocytes at low 02 concentration. J Biol Chem 257: 8997–9004PubMedGoogle Scholar
  6. Aw TY, Jones DP (1984) Control of glucuronidation during hypoxia: limitation by UDP-glucose pyrophosphorylase. Biochem J 219: 707–712PubMedGoogle Scholar
  7. Babson JR, Reed DJ (1978) Inactivation of glutathione reductase by 2-chloroethyl nitrosourea-derived isocyanates. Biochem Biophys Res Commun 83: 754–762PubMedCrossRefGoogle Scholar
  8. Bänhegyi G, Garzo T, Antoni F, Mandl J (1988) Glycogenolysis - and not gluconeogenesis - is the source of UDP-glucuronic acid for glucuronidation. Biochim Biophys Acta 967: 429–435PubMedCrossRefGoogle Scholar
  9. Bänhegyi G, Puskäs R, Garzö T, Antoni F, Mandl J (1991) High amounts of glucose and insulin inhibit p-nitrophenol conjugation in mouse hepatocytes. Biochem Pharmacol 42: 1299–1302PubMedCrossRefGoogle Scholar
  10. Beck LV, Linkenheimer W (1952) Effects of shock and cold on mouse liver sulfhydryls. Proc Soc Exp Biol Med 81: 291–294PubMedGoogle Scholar
  11. Bock KW, Fröhling W, Remmer H, Rexer B (1973) Effects of phenobarbital and 3-methylcholanthrene on substrate specificity of rat liver microsomal UDPglucuronyltransferase. Biochim Biophys Acta 327: 46–56PubMedGoogle Scholar
  12. Bock KW, Huber E, Schlote W (1977) UDP-glucuronytransferase in perfused rat liver and in microsomes. Effects of CC14 injury. Naunyn Schmiedebergs Arch Pharmacol 296: 199–203PubMedCrossRefGoogle Scholar
  13. Brzeznicka EA, Hazelton GA, Klaassen CD (1987) Comparison of adenosine 3’-phosphate 5’-phosphosulfate concentrations in tissues from different laboratory animals. Drug Metab Dispos 15: 133–135PubMedGoogle Scholar
  14. Buckpitt AR, Rollins DE, Mitchell JR (1979) Varying effects of sulfhydryl nucleophiles on acetaminophen oxidation and sulfhydryl adduct formation. Biochem Pharmacol 28: 2941–2946PubMedCrossRefGoogle Scholar
  15. Chen T, Richie JP, Lang CA (1990) Life span profiles of glutathione and acetaminophen detoxification. Drug Metab Dispos 18: 882–887PubMedGoogle Scholar
  16. Comporti M (1987) Glutathione depleting agents and lipid peroxidation. Chem Phys Lipids 45: 143–169PubMedCrossRefGoogle Scholar
  17. Connor HD, LaCagnin LB, Knecht KT, Thurman RG, Mason RP (1990) Reaction of glutathione with a free radical metabolite of carbon tetrachloride. Mol Pharmacol 37: 443–451PubMedGoogle Scholar
  18. Conway JG, Kauffman FC, Thurman RG (1985) Effect of glucose on 7-hydroxycoumarin glucuronide production in periportal and pericentral regions of the liver lobule. Biochem J 226: 749–756PubMedGoogle Scholar
  19. Dills RL, Klaassen CD (1984) Decreased glucuronidation of bilirubin by diethyl ether anesthesia. Biochem Pharmacol 33: 2813–2814PubMedCrossRefGoogle Scholar
  20. Dills RL, Klaassen CD (1986a) The effect of inhibitors of mitochondrial energy production on hepatic glutathione, UDP-glucuronic acid, and adenosine 3’-phosphate-5’-phosphosulfate concentrations. Drug Metab Dispos 14: 190–196PubMedGoogle Scholar
  21. Dills RL, Klaassen CD (1986b) Effect of reduced hepatic energy state on acetaminophen conjugation in rats. J Pharmacol Exp Ther 238: 463–472PubMedGoogle Scholar
  22. Dutton GJ (ed) (1980) Glucuronidation of drugs and other compounds. CRC, Boca RatonGoogle Scholar
  23. Dziewiatkowski DD, Lewis HB (1944) Glucuronic acid synthesis and the glycogen content of the liver of the rat. J Biol Chem 153: 49–52Google Scholar
  24. Eacho PI, Sweeny D, Weiner M (1981a) Effects of glucose and fructose on conjugation of β-nitrophenol in hepatocytes of normal and streptozotocin-diabetic rats. Biochem Pharmacol 30: 2616–2619PubMedCrossRefGoogle Scholar
  25. Eacho PI, Sweeny D, Weiner M (1981b) Conjugation of p-nitroanisole and p-nitrophenol in hepatocytes isolated from streptozotocin diabetic rats. J Pharmacol Exp Ther 218: 34–40PubMedGoogle Scholar
  26. Friedel HA, Goa KL, Benfield P (1989) S-Adenosyl-L-methionine: a review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs 38: 389–416PubMedCrossRefGoogle Scholar
  27. Galinsky RE (1986) Role of glutathione turnover in drug sulfation: differential effects of diethylmaleate and buthionine sulfoximine on the pharmacokinetics of acetaminophen in the rat. J Pharmacol Exp Ther 236: 133–139PubMedGoogle Scholar
  28. Galinsky RE, Levy G (1981) Dose- and time-dependent elimination of acetaminophen in rats: pharmacokinetic implications of cosubstrate depletion. J Pharmacol Exp Ther 219: 14–20PubMedGoogle Scholar
  29. Goon D, Klaassen CD (1992) Effects of microsomal enzyme inducers upon UDPglucuronic acid concentration and UDP-glucuronosyltransferase activity in the rat intestine and liver. Toxicol Appl Pharmacol 115: 254–260CrossRefGoogle Scholar
  30. Greenbaum AL, Gumaa KA, McLean P (1971) The distribution of hepatic metabolites and the control of the pathways of carbohydrate metabolism in animals of different dietary and hormonal status. Arch Biochem Biophys 143: 617–663PubMedCrossRefGoogle Scholar
  31. Gregus Z, White C, Howell S, Klaassen CD (1988a) Effect of glutathione depletion on sulfate activation and sulfate ester formation in rats. Biochem Pharmacol 37: 4307–4312PubMedCrossRefGoogle Scholar
  32. Gregus Z, Madhu C, Goon D, Klaassen CD (1988b) Effect of galactosamineinduced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats: dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals. Drug Metab Dispos 16: 527–533PubMedGoogle Scholar
  33. Griffeth LK, Rosen GM, Rauckman EJ (1985) Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation. Drug Metab Dispos 13: 391–397Google Scholar
  34. Hauser SC, Ransil BJ, Ziurys JC, Gollan JL (1988a) Interaction of uridine 5’-diphosphoglucuronic acid with microsomal UDP-glucuronosyltransferase in primate liver: the facilitating role of uridine 5’-diphospho-N-acetylglucosamine. Biochim Biophys Acta 967: 141–148PubMedCrossRefGoogle Scholar
  35. Hauser SC, Ziurys JC, Gollan JL (1988b) A membrane transporter mediates access of uridine 5’-diphosphoglucuronic acid from the cytosol into the endoplasmic reticulum of rat hepatocytes: implications for glucuronidation reactions. Biochim Biophys Acta 967: 149–157PubMedCrossRefGoogle Scholar
  36. Hellerstein MK, Wu K, Kaempfer S, Kletke C, Shackleton CHL (1991) Sampling the lipogenic hepatic acetyl-CoA pool in vivo in the rat: comparison of xenobiotic probe to values predicted from isotopomeric distribution in circulating lipids and measurement of lipogenesis and acetyl-CoA dilution. J Biol Chem 266: 10912–10919PubMedGoogle Scholar
  37. Hill KE, Burk RF (1982) Effect of selenium deficiency and vitamin E deficiency on glutathione metabolism in isolated rat hepatocytes. J Biol Chem 257: 10668–10672Google Scholar
  38. Hjelle JJ, Hazelton GA, Klaassen CD (1985) Acetaminophen decreases adenosine 3’-phosphate 5’-phosphosulfate and uridine diphosphoglucuronic acid in rat liver. Drug Metab Dispos 13: 35–41PubMedGoogle Scholar
  39. Howell SR, Hazelton GA, Klaassen CD (1986) Depletion of hepatic UDP-glucuronic acid by drugs that are glucuronidated. J Pharmacol Exp Ther 236: 610–614PubMedGoogle Scholar
  40. James RC, Roberts SM, Harbison RD (1983) The perturbation of hepatic glutathione by a2-adrenergic agonists. Fundam Appl Toxicol 3: 303–308PubMedCrossRefGoogle Scholar
  41. Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 187: 195–202Google Scholar
  42. Jones DP (1984) Benzylamine metabolism at low 02 concentrations: relative sensitivities of monoamine oxidase, aldehyde dehydrogenase and hippurate synthesis to hypoxia. Biochem Pharmacol 33: 413–417PubMedCrossRefGoogle Scholar
  43. Kamisako T, Adachi Y, Yamamoto T (1990) Effect of UDP-glucuronic acid depletion by salicylamide on biliary bilirubin excretion in the rat. J Pharmacol Exp Ther 254: 380–382PubMedGoogle Scholar
  44. Kaplowitz N, Aw TY, Ookhtens M (1985) The regulation of hepatic glutathione. Annu Rev Pharmacol Toxicol 25: 715–744PubMedCrossRefGoogle Scholar
  45. Kim HJ, Rozman P, Madhu C, Klaassen CD (1992) Homeostasis of sulfate and 3’- phosphoadenosine 5’-phosphosulfate in rats after acetaminophen administration. J Pharmacol Exp Ther 261: 1015–1021PubMedGoogle Scholar
  46. Koster H, Halsema I, Scholtens E, Knippers M, Mulder GJ (1981) Dose-dependent shifts in the sulfation and glucuronidation of phenolic compounds in the rat in vivo and in isolated hepatocytes: the role of saturation of phenolsulfotransferase. Biochem Pharmacol 18: 2569–2575CrossRefGoogle Scholar
  47. Koster H, Mulder GJ (1982) Apparent aberrancy in the kinetics of intracellular metabolism of a single substrate by two enzymes: an alternative explanation for anomalies in the kinetics of sulfation and glucuronidation. Drug Metab Dispos 10: 330–335PubMedGoogle Scholar
  48. Krijgsheld KR, Scholtens E, Mulder GJ (1981a) An evaluation of methods to decrease the availability of inorganic sulphate for sulphate conjugation in the rat in vivo. Biochem Pharmacol 30: 1973–1979CrossRefGoogle Scholar
  49. Krijgsheld KR, Glazenburg EJ, Scholtens E, Mulder GJ (1981b) The oxidation of Land D-cysteine to inorganic sulfate and taurine in the rat. Biochim Biophys Acta 677: 7–12PubMedCrossRefGoogle Scholar
  50. Larsson A, Orrenius S, Holmgren A, Mannervik B (eds) (1983) Functions of glutathione: biochemical, physiological, toxicological, and clinical aspects. Raven, New YorkGoogle Scholar
  51. Lauterburg BH, Mitchell JR (1980) In vivo regulation of hepatic glutathione synthesis: effects of food deprivation or glutathione depletion by electrophilic compounds. In: Snyder R, Parke DV, Kocsis JJ, Jollow DJ, Bogson CG, Witmer CM (eds) Biological reactive intermediates - II: chemical mechanisms and biological effects. Adv Exp Med Biol 136A: 453Google Scholar
  52. Lauterburg BH, Adams JD, Mitchell JR (1984) Hepatic glutathione homeostasis in the rat: efflux accounts for glutathione turnover. Hepatology 4: 586–590PubMedCrossRefGoogle Scholar
  53. Lin JH, Levy G (1986) Effect of prevention of inorganic sulfate depletion on the pharmacokinetics of acetaminophen in rats. J Pharmacol Exp Ther 239: 94–98PubMedGoogle Scholar
  54. Massey TE, Racz WJ (1981) Effects of N-acetylcysteine on metabolism, covalent binding, and toxicity of acetaminophen in isolated mouse hepatocytes. Toxicol Appl Pharmacol 60: 220–228PubMedCrossRefGoogle Scholar
  55. Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263: 17205–17208PubMedGoogle Scholar
  56. Meister A (1991) Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther 51: 155–194PubMedCrossRefGoogle Scholar
  57. Minck K, Schupp RR, Illing PA, Kahl GF, Netter KJ (1973) Interrelationship between demethylation of p-nitroanisole and conjugation of p–nitrophenol in rat liver. Naunyn Schmiedebergs Arch Pharmacol 279: 347–360PubMedCrossRefGoogle Scholar
  58. Miners JO, Mackenzie PI (1991) Drug glucuronidation in humans. Pharmacol Ther 51: 347–369PubMedCrossRefGoogle Scholar
  59. Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Drug metabolism as a cause of drug toxicity. Drug Metab Dispos 1: 418–423PubMedGoogle Scholar
  60. Moldeus P, Andersson B, Nor ling A (1978) Interaction of ethanol oxidation with glucuronidation in isolated hepatocytes. Biochem Pharmacol 27: 2583–2588PubMedCrossRefGoogle Scholar
  61. Moldeus P, Andersson B, Gergely V (1979) Regulation of glucuronidation and sulfate conjugation in isolated hepatocytes. Drug Metab Dispos 7: 416–419PubMedGoogle Scholar
  62. Mulder GJ (1981) Sulfate activation. In: Mulder GJ (ed) Sulfation of drugs and related compounds. CRC, Boca Raton, p 53Google Scholar
  63. Paterson P, Fry JR (1983) The effect of ascorbic acid on the conjugation of 4-hydroxybiphenyl in rat isolated hepatocytes. Xenobiotica 13: 607–610PubMedCrossRefGoogle Scholar
  64. Plummer JL, Smith BR, Sies H, Bend JR (1981) Chemical depletion of glutathione in vivo. In: Jacoby WB (ed) Detoxication and drug metabolism: conjugation and related systems. Methods Enzymol 77: 50CrossRefGoogle Scholar
  65. Polhuijs M, Lankhaar G, Mulder GJ (1992) Relationship between glutathione content in liver and glutathione conjugation rate in the rat in vivo. Effect of buthionine sulphoximine pre treatment on conjugation of the two 2-bromoisovalerylurea enantiomers during intravenous infusion. Biochem J 285: 401–404PubMedGoogle Scholar
  66. Price VF, Jollow DJ (1982) Increased resistance of diabetic rats to aeetaminopheninduced hepatotoxicity. J Pharmacol Exp Ther 220: 504–513PubMedGoogle Scholar
  67. Price VF, Jollow DJ (1986) Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity. Biochem Pharmacol 35: 687–695PubMedCrossRefGoogle Scholar
  68. Price VF, Miller MG, Jollow DJ (1987) Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat. Biochem Pharmacol 36: 427–433PubMedCrossRefGoogle Scholar
  69. Price VF, Jollow DJ (1988) Mechanism of decreased acetaminophen glucuronidation in the fasted rat. Biochem Pharmacol 37: 1067–1075PubMedCrossRefGoogle Scholar
  70. Price VF, Jollow DJ (1989) Effect of glucose and gluconeogenic substrates on fasting-induced suppression of acetaminophen glucuronidation in the rat. Biochem Pharmacol 38: 289–297PubMedCrossRefGoogle Scholar
  71. Pyke S, Lew H, Quintanilha A (1986) Severe depletion in liver glutathione during physical exercise. Biochem Biophys Res Commun 139: 926–931PubMedCrossRefGoogle Scholar
  72. Reinke LA, Belinsky SA, Evans RK, Kauffman FC, Thurman RG (1981) Conjugation of p-nitrophenol in the perfused rat liver: the effect of substrate concentration and carbohydrate reserves. J Pharmacol Exp Ther 217: 863–870PubMedGoogle Scholar
  73. Reinke LA, Moyer MJ, Notley KA (1986) Diminished rates of glucuronidation and sulfation in perfused rat liver after chronic ethanol administration. Biochem Pharmacol 35: 439–447PubMedCrossRefGoogle Scholar
  74. Reinke LA, Tupper JS, Sweeny DJ (1987) 7-Ethoxycoumarin O-deethylation in perfused livers from ethanol-fed rats: evidence for an important role of mitochondrial reducing equivalents. Pharmacology 34:167–175Google Scholar
  75. Ross D (1988) Glutathione, free radicals and chemotherapeutic agents: mechanisms of free-radical induced toxicity and glutathione-dependent protection. Pharmacol Ther 37: 231–249PubMedCrossRefGoogle Scholar
  76. Roy AB (1981) Sulfotransferases. In: Mulder GJ (ed) Sulfation of drugs and related compounds. CRC, Boca Raton, p 83Google Scholar
  77. Rozman P, Kim HJ, Madhu C, Gregus A, Klaassen CD (1992) Homeostasis of sulfate and 3’-phosphoadenosine 5’-phosphosulfate in rats with deficient dietary intake of sulfur. Drug Metab Dispos 20: 374–378PubMedGoogle Scholar
  78. Schwarz LR (1980) Modulation of sulfation and glucuronidation of 1-naphthol in isolated rat liver cells. Arch Toxicol 44: 137–145PubMedCrossRefGoogle Scholar
  79. Schwarz LR (1984) Sulfation of 1-naphthol in isolated rat hepatocytes: dependence on inorganic sulfate. Hoppe Seylers Z Physiol Chem 365: 43–48PubMedCrossRefGoogle Scholar
  80. Shipley LA, Weiner M (1987) Effects of adenosine on glucuronidation and uridine diphosphate glucuronic acid ( UDPGA) synthesis in isolated hepatocytes. Biochem Pharmacol 36: 2993–3000Google Scholar
  81. Shipley LA, Eacho PI, Sweeny DJ, Weiner M (1986) Inhibition of glucuronidation and sulfation by dibutyryl cyclic AMP in isolated rat hepatocytes. Drug Metab Dispos 14: 526–531PubMedGoogle Scholar
  82. Sies H (1985) Hydroperoxides and thiol oxidants in the study of oxidative stress in intact cells and organs. In: Sies H (ed) Oxidative stress. Academic, London, p 73Google Scholar
  83. Sies H, Wendel A (eds) (1978) Functions of glutathione in liver and kidney. Springer, Berlin Heidelberg New YorkGoogle Scholar
  84. Sies H, Brigelius R, Weiers H, Muller A, Cadenas E (1983) Cellular redox changes and response to drugs and toxic agents. Fundam Appl Toxicol 3: 200–208PubMedCrossRefGoogle Scholar
  85. Singh J, Schwarz LR (1981) Dependence of glucuronidation rate on UDP-glucuronic acid levels in isolated hepatocytes. Biochem Pharmacol 30: 3252–3254PubMedCrossRefGoogle Scholar
  86. Stipanuk MH, Coloso RM, Garcia RAG, Banks MF (1992) Cysteine concentration regulates cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes. J Nutr 122: 420–427PubMedGoogle Scholar
  87. Sun Y, Cotgreave I, Lindeke B, Moldeus P (1989) The metabolism of sulfite in liver: stimulation of sulfate conjugation and effects on paracetamol and allyl alcohol toxicity. Biochem Pharmacol 38: 4299–4305PubMedCrossRefGoogle Scholar
  88. Sundheimer DW, Brendel K (1984) Factors influencing sulfation in isolated rat hepatocytes. Life Sei 34: 23–29CrossRefGoogle Scholar
  89. Sweeny DJ, Reinke LA (1988) Sulfation of acetaminophen in isolated rat hepatocytes: relationship to sulfate ion concentrations and intracellular levels of 3’-phosphoadenosine-5’-phosphosulfate. Drug Metab Dispos 16: 712–715PubMedGoogle Scholar
  90. Thurman RG, Ganey PE, Belinsky SA, Conway JG, Badr MZ, Kauffman FC (1989) Advantages of the perfused liver as a model to study hepatotoxicity in periportal and pericentral regions of the liver lobule. In: McQueen CA (ed) In vitro toxicology: model systems and methods. Telford, London, p 69Google Scholar
  91. Tribble DL, Jones DP (1990) Oxygen dependence of oxidative stress: rate of NADPH supply for maintaining the GSH pool during hypoxia. Biochem Pharmacol 39: 729–736PubMedCrossRefGoogle Scholar
  92. Watkins JB, Klaassen CD (1983) Chemically-induced alteration of UDP-glucuronic acid concentration in rat liver. Drug Metab Dispos 11: 37–40PubMedGoogle Scholar
  93. Watkins JB, Siegers C-P, Klaassen CD (1984) Effect of diethyl ether on the biliary excretion of acetaminophen. Proc Soc Exp Biol Med 177: 168–175PubMedGoogle Scholar
  94. Watkins JB, Engles DR, Beck LV (1990) Effect of volatile anesthetics on the hepatic UDP-glucuronic acid pathway in mice. Biochem Pharmacol 40: 731–735PubMedCrossRefGoogle Scholar
  95. Wiebkin P, Parker GL, Fry JR, Bridges JW (1979) Effect of various metabolic inhibitors on biphenyl metabolism in isolated rat hepatocytes. Biochem Pharmacol 28: 3315–3321PubMedCrossRefGoogle Scholar
  96. Wu I-R, Kauffman FC, Qu W, Ganey P, Thurman RG (1990) Unique role of oxygen in regulation of hepatic monooxygenation and glucuronidation. Mol Pharmacol 38: 128–133PubMedGoogle Scholar
  97. Zakim D, Dannenberg AJ (1992) How does the microsomal membrane regulate UDP-glucuronosyltransferases? Biochem Pharmacol 43: 1385–1393PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • L. A. Reinke
  • F. C. Kauffmann
  • R. G. Thurman

There are no affiliations available

Personalised recommendations