Thiopurine methyltransferase activity in a Spanish population sample: decrease of enzymatic activity in multiple sclerosis patients

Abstract

The present study was performed in order to obtain the thiopurine methyltransferase (TPMT) activity frequency distribution histogram in a Spanish population. A total of 3640 Spanish clinical laboratory samples were evaluated, which included 1249 patients with Crohn’s disease, 589 with ulcerative colitis, 348 with multiple sclerosis (MS), 487 with several autoimmune diseases different from the above-mentioned diseases and 967 a donor group. We have measured the TPMT activity in red blood cells (RBCs) by a radiochemical method, using S-adenosyl-L-[methyl-³H]methionine as methyl donor. The different groups present in their entirety a normal distribution histogram and a wide range of TPMT activity from 0 to 41 U/ml RBCs. The differences found between the Spanish population TPMT activity frequency distribution histogram and the pattern previously described in a North American population were not due to azathioprine treatment or gender. The effect of autoimmune diseases on TPMT activity was evaluated: the enzymatic activity was similar in the donor group (19.9-6.3 U/ml RBCs) and in the patients with Crohn’s disease (20.0-5.8 U/ml RBCs) and ulcerative colitis (19.7-6.1 U/ml RBCs); however, it decreased significantly (p<0.0001) in MS patients (17.1-6.1 U/ml RBCs) with respect to the donor group. In conclusion, our results show that the Spanish population TPMT distribution is closer to that of the Jewish population of Israel than to North American populations, and that in MS the enzymatic activity of TPMT decreases significantly. This observation may take into account the usage of azathioprine as therapeutic agent in Spanish MS patients.

Keywords

Crohn's disease erythrocyte multiple sclerosis polymorphism thiopurine methyltransferase ulcerative colitis

Get full access to this article

View all access options for this article.

References

Remy CN. Metabolism of thiopyrimidines and thiopurines: S-methylation with S-adenosylmethionine transmethylase and catabolism in mammalian tissue . J Biol Chem 1963; 238: 1078-1084 .

Woodson LC , Weinshilboum RM. Human kidney thiopurine methyltransferase: purification and biochemical properties . Biochem Pharmacol 1983; 32: 819-826 .

Ames MM , Selassie CD , Woodson LC , Van Loon JA , Hansch C , Weinshilboum RM. Thiopurine methyltransferase: structure-activity relationships for benzoic acid inhibitors and thiophenol substrates . J Med Chem 1986; 29: 354-358 .

Szumlanski CL , Scott MC , Weinshilboum RM. Thiopurine methyltransferase pharmacogenetics: human liver enzyme activity . Clin Pharmacol Ther 1988; 43: 134-134 .

Klemetsdal B , Tollefsen E , Loennechen T , et al. Interethnic difference in thiopurine methyltransferase activity . Clin Pharmacol Ther 1992; 51: 24-31 .

Park-Hah JO , Klemetsdal B , Lysaa R , Choi KH , Aarbakke J. Thiopurine methyltransferase activity in a Korean population sample of children . Clin Pharmacol Ther 1996; 60: 68-72 .

McLeod HL , Lin JS , Scott EP , Pui CH , Evans WE. Thiopurine methyltransferase activity in American white subject and black subjects . Clin Pharmacol Ther 1994; 55: 15-20 .

Otterness D , Szumlanski C , Lennard L , et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphism . Clin Pharmacol Ther 1997; 62: 60-73 .

Szumlanski C , Otterness D , Her C , et al. Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism . DNA Cell Biol 1996; 15: 17-30 .

10.

Szumlanski CL , Honchel R , Scott MC , Weinshilboum RM. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver erythrocyte correlation and presence of isozymes . Pharmacogenetics 1992; 2: 148-159 .

11.

Escousse A , Mousson C , Santona L , et al. Azathioprine-induced pancytopenia in homozygous thiopurine methyltransferase-deficient renal transplant recipient: a family study . Transplant Proc 1995; 27: 1739-1742 .

12.

Dervieux T , Medard Y , Baudouin V , et al. Thiopurine methyltranferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine . Br J Clin Pharmacol 1999; 48: 793-800 .

13.

Relling MV , Hancock ML , Boyett JM , Pui CH , Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia . Blood 1999; 93: 2817-2823 .

14.

Weinshilboum RM , Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity . Am J Hum Genet 1980; 32: 651-662 .

15.

Menor C , Fueyo JA , Escribano D , et al. Determination of thiopurine methyltransferase activity in human erythrocytes by HPLC. Comparison with the radiochemical method . Ther Drug Monitor 2001; 23: 536-541 .

16.

Yan L , Zhang S , Eiff B , et al. Thiopurine methyl transferase polymorphic tandem repeat: genotype-phenotype correlation analysis . Clin Pharmacol Ther 2000; 68: 210-219 .

17.

Snow JL , Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients . Arch Dermatol 1995; 131: 193-197 .

18.

Lowenthal A , Meyerstein N , Ben-Zvi Z. Thiopurine methyltransferase activity in the Jewish population of Israel . Eur J Clin Pharmacol 2001; 57: 43-46 .

19.

Spire-Vayron de la Moureyre C , Debuysere H , Mastain B , et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population . Br J Pharmacol 1998; 125: 879-887 .

20.

Kröplin T , Weyer N , Gutsche S , Iven H. Thiopurine S-methyltransferase activity in human erythrocytes: a new HPLC method using 6-thioguanine as substrate . Eur J Clin Pharmacol 1998; 54: 265-271 .

21.

Thervet E , Anglicheau D , Toledano N , et al. Long-term results of TPMT activity monitoring in azathioprine-treated renal allograft recipients . J Am Soc Nephrol 2001; 12: 170-176 .

22.

Pazmino PA , Sladek SL , Weinshilboum RM. Thiol S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors . Clin Pharmacol Ther 1980; 28: 356-367 .

23.

Zeng SM , Yankowitz J , Widness JA , Strauss RG. Etiology of differences in hematocrit between males and females: sequence-based polymorphisms in erythropoietin and its receptor . J Gender Specif Med 2001; 4: 35-40 .

24.

Decaux G , Horsmans Y , Houssiau F , Desager JP. High 6- thioguanine nucleotide levels and low thiopurine methyltransferase activity in patients with lupus erythematosus treated with azathioprine . Am J Ther 2001; 8: 147-150 .

25.

Relling MV , Rubnitz JE , Rivera GK , et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites . Lancet 1999; 354: 34-39 .

26.

Compston A. Genetic susceptibility to multiple sclerosis. In Compston A ed. McAlpine’s multiple sclerosis, third edition. London: Churchill Livingstone , 1999: 101-142.

27.

Robertson DM , Dinsdale HB , Campbell RJ. Subacute combined degeneration of the spinal cord. No association with vitamin B12 deficiency . Arch Neurol 1971; 24: 203-209 .

28.

Lever EG , Elwes RD , Williams A , Reynolds EH. Subacute combined degeneration of the spinal cord. Due to folate deficiency: response to methyl folate treatment . J Neurol Neurosurg Psychiatry 1986; 49: 1203-1207 .

29.

Surtees R , Leonard J , Austin S. Association of demyelination with deficiency of cerebrospinal fluid S-adenosyl methionine in inborn errors of methyl-transfer pathways . Lancet 1991; 338: 1550-1554 .

30.

Chamberlain M , Ubagai T , Mudd SH , Wilson WG , Leonard JV. Demyelination of the brain is associated with methionine adenosyl transferase I/III deficiency . J Clin Invest 1996; 98: 1021-1027 .

31.

Surtees R , Clelland J , Hann I. Demyelination and single carbon transfer pathways metabolites during the treatment of acute lymphoblastic leukaemia: CSF studies . J Clin Oncol 1998; 16: 1505-1511 .

32.

Kishi T , Tanaka Y , Ueda K. Evidence for hypomethylation in two children with acute lymphoblastic leukaemia and leukoencephalopathy . Cancer 2000; 89: 925-931 .

33.

Pritzker LB , Joshi S , Haranz G , Moscarello MA. Deimination of myelin basic protein.2. Effect of methylation of MBP on its deimination by peptidylarginine deiminase . Biochemistry 2000; 39: 5382-5388 .

34.

Young PR , Vacante DA , Waickus M. Mechanism of interaction between myelin basic protein and the myelin membrane; the role of arginine methylation . Biochem Biophys Res Commun 1987; 145: 1112-1118 .

35.

Pritzker LB , Joshi S , Gowam JJ , Haranz G , Moscarello MA. Deimination of myelin basic protein: 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D . Biochemistry 2000; 39: 5374-5381 .

36.

Warren KG , Catz I. Kinetic profiles of cerebrospinal fluid anti-MBP in response to intravenous MBP synthetic peptide DENP(85) VVHFFKNIVTP(96)RT in multiple sclerosis patients . Mult Scler 2000; 6: 300-311 .

37.

Goodkin DE , Jacobsen DW , Galvez N , Daughtry M , Secic M , Green R. Serum cobalamin is uncommon in multiple sclerosis . Arch Neurol 1994; 51: 1110-1114 .

38.

Palace J , Rothwell P. New treatments and azathioprine in multiple sclerosis . Lancet 1997; 350: 261-261 .

39.

Salmaggi A , Corsini E , La Mantia , et al. Immunological monitoring of azathioprine treatment in multiple sclerosis patients . J Neurol 1997; 244: 167-174 .