GENETIC POLYMORPHISMS IN HUMAN LIVER PHENOL SULFOTRANSFERASES INVOLVED IN THE BIOACTIVATION OF N-HYDROXY DERIVATIVES OF CARCINOGENIC ARYLAMINES AND HETEROCYCLIC AMINES

Three related forms of phenol sulfotransferase (PSULT), thermostable S T1A2 (SULT1A2hum) and ST1A3 (SULT1A1hum) and a thermolabile TL-PST (SU LT1A3hum), are known to exist in human livers. Thermostable forms, who se activities are polymorphically distributed, have been shown to medi ate the bioactivation of carcinogenic N-hydroxy arylamines and heteroc yclic amines. To clarify the nature of the sulfation polymorphism, the study compared the expressed levels of ST1A2, ST1A3 and TL-PST mRNAs in human livers by the method of reverse-transcriptase polymerase chai n reaction (RT-PCR), utilizing HindIII, BamHI and SnaBI sites which we re unique to the above PSULT cDNAs, respectively. Of the PCR products derived from human liver (n = 26), 43-89, < 1-29 and < 1-21% showed th e restriction pattern characteristic for ST1A3, ST1A2 and TL-PST cDNAs , respectively, thus indicating that ST1A3 mRNA is the major transcrip t. Hepatic p-nitrophenol and dopamine sulfation rates ranged from 440- 2670 and < 5-460 pmol/min per mg protein in the 26 individuals, respec tively. The observed differences in the ST1A3 and TL-PST mRNA levels w ere consistent with the differences in p-nitrophenol and dopamine sulf ations. Relative levels of hepatic ST1A3 mRNA were non-normally distri buted and correlated significantly with p-nitrophenol sulfation. In ad dition, variant forms of ST1A3 mRNA encoding Arg213His and Met223Val w ere detected in human livers. With regard to Arg213His, 28 individuals who had homozygous (213)Arg alleles, 15 individuals who were heterozy gotes and nine homozygous (213)His individuals were found by a newly e stablished genotyping method among 52 human liver samples. Frequency o f (223)Val allele was apparently lower than that of (213)His allele, a s no homozygous (223)Val individual and only three individuals who wer e heterozygotes ((223)Met/Val) were observed among 52 individuals. The se results suggest that regulation of p-nitraphenol sulfation occurs a t the level of gene transcription of ST1A3 which is the major transcri pt of the three PSULT mRNAs and that a polygenic basis for the apparen t genetic polymorphism of sulfation was likely because of the existenc e of ST1A3 variants. Published by Elsevier Science Ireland Ltd.