TY - JOUR
T1 - Human phenol sulfotransferases SULT1A2 and SULT1A1 Genetic polymorphisms, allozyme properties, and human liver genotype-phenotype correlations
AU - Raftogianis, Rebecca B.
AU - Wood, Thomas C.
AU - Weinshilboum, Richard M.
N1 - Funding Information:
We thank Diane Otterness for her advice and Luanne Wussow for her assistance with the preparation of this manuscript. This work was supported, in part, by NIH Grants RO1 GM35720 (R. M. W.) and RO1 GM28157 (R. M. W.) and by NRSA Individual Postdoctoral Fellowship GM18800 (R. B. R.).
PY - 1999/8/15
Y1 - 1999/8/15
N2 - Phenol sulfotransferases (PSTs or phenol SULTs) catalyze the sulfate conjugation of phenolic drugs, xenobiotics, and monoamines. Two human PST isoforms have been defined biochemically, a thermostable (TS), or phenol-preferring, and a thermolabile (TL), or monoamine-preferring form. Pharmacogenetic studies showed that levels of both TS PST activity and TS PST thermal stability (an indirect measure of variation in amino acid sequence) in the platelet were regulated by genetic polymorphisms. Subsequent molecular genetic experiments revealed the existence of three human PST genes, two of which, SULT1A1 and SULT1A2, encode proteins with 'TS PST-like' activity. We recently reported common nucleotide polymorphisms for SULT1A1 that are associated with variations in platelet TS PST activity and thermal stability. In the present experiments, we set out to determine whether functionally significant DNA polymorphisms also might exist for SULT1A2, to compare the biochemical properties of all common allozymes encoded by SULT1A2 and SULT1A1, and to study phenol SULT genotype-phenotype correlations in the human liver. We phenotyped 61 human liver biopsy samples for TS PST thermal stability and activity. The open reading frames of SULT1A2 and SULT1A1 then were amplified with the polymerase chain reaction and sequenced for each of these hepatic tissue samples. We observed 13 SULT1A2 alleles that encoded 6 allozymes. These alleles were in linkage disequilibrium with alleles for SULT1A1. Biochemical characterization of common allozymes encoded by both genes suggested that SULT1A1 was primarily responsible for 'TS PST phenotype' in the human liver. In summary, both SULT1A2 and SULT1A1 have a series of common alleles encoding enzymes that differ functionally and are associated with individual differences in phenol SULT properties in the liver. Copyright (C) 1999 Elsevier Science Inc.
AB - Phenol sulfotransferases (PSTs or phenol SULTs) catalyze the sulfate conjugation of phenolic drugs, xenobiotics, and monoamines. Two human PST isoforms have been defined biochemically, a thermostable (TS), or phenol-preferring, and a thermolabile (TL), or monoamine-preferring form. Pharmacogenetic studies showed that levels of both TS PST activity and TS PST thermal stability (an indirect measure of variation in amino acid sequence) in the platelet were regulated by genetic polymorphisms. Subsequent molecular genetic experiments revealed the existence of three human PST genes, two of which, SULT1A1 and SULT1A2, encode proteins with 'TS PST-like' activity. We recently reported common nucleotide polymorphisms for SULT1A1 that are associated with variations in platelet TS PST activity and thermal stability. In the present experiments, we set out to determine whether functionally significant DNA polymorphisms also might exist for SULT1A2, to compare the biochemical properties of all common allozymes encoded by SULT1A2 and SULT1A1, and to study phenol SULT genotype-phenotype correlations in the human liver. We phenotyped 61 human liver biopsy samples for TS PST thermal stability and activity. The open reading frames of SULT1A2 and SULT1A1 then were amplified with the polymerase chain reaction and sequenced for each of these hepatic tissue samples. We observed 13 SULT1A2 alleles that encoded 6 allozymes. These alleles were in linkage disequilibrium with alleles for SULT1A1. Biochemical characterization of common allozymes encoded by both genes suggested that SULT1A1 was primarily responsible for 'TS PST phenotype' in the human liver. In summary, both SULT1A2 and SULT1A1 have a series of common alleles encoding enzymes that differ functionally and are associated with individual differences in phenol SULT properties in the liver. Copyright (C) 1999 Elsevier Science Inc.
KW - Genetic polymorphism
KW - Pharmacogenetics
KW - SULT1A1
KW - SULT1A2
KW - Sulfotransferase
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U2 - 10.1016/S0006-2952(99)00145-8
DO - 10.1016/S0006-2952(99)00145-8
M3 - Article
C2 - 10413297
AN - SCOPUS:0033567437
SN - 0006-2952
VL - 58
SP - 605
EP - 616
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -