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 ST1A2 (SULT1A2hum) and ST1A3 (SULT1A1hum) and a thermolabile TL-PST (SULT1A3hum), are known to exist in human livers. Thermostable forms, whose activities are polymorphically distributed, have been shown to mediate the bioactivation of carcinogenic N-hydroxy arylamines and heterocyclic 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 chain reaction (RT-PCR), utilizing HindIII, BamHI and SnaBI sites which were 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 the restriction pattern characteristic for ST1A3, ST1A2 and TL-PST cDNAs, respectively, thus indicating that ST1A3 mRNA is the major transcript. Hepatic p-nitrophenol and dopamine sulfation rates ranged from 440-2670 and < 5-460 pmol/min per mg protein in the 26 individuals, respectively. The observed differences in the ST1A3 and TL-PST mRNA levels were consistent with the differences in p-nitrophenol and dopamine sulfations. Relative levels of hepatic ST1A3 mRNA were non-normally distributed and correlated significantly with p-nitrophenol sulfation. In addition, variant forms of ST1A3 mRNA encoding Arg213His and Met223Val were detected in human livers. With regard to Arg213His, 28 individuals who had homozygous 213Arg alleles, 15 individuals who were heterozygotes and nine homozygous 213His individuals were found by a newly established genotyping method among 52 human liver samples. Frequency of 223Val allele was apparently lower than that of 213His allele, as no homozygous 223Val individual and only three individuals who were heterozygotes (223Met/Val) were observed among 52 individuals. These results suggest that regulation of p-nitrophenol sulfation occurs at the level of gene transcription of ST1A3 which is the major transcript of the three PSULT mRNAs and that a polygenic basis for the apparent genetic polymorphism of sulfation was likely because of the existence of ST1A3 variants.
Ozawa
S
S
Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, AR, USA.
Tang
Y M
YM
Yamazoe
Y
Y
Kato
R
R
Lang
N P
NP
Kadlubar
F F
FF
D000588:Amines / Q000493:pharmacokinetics*; D015239:Arylsulfotransferase / Q000235:genetics* / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D005838:Genotype; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic
D000588:Amines; D002273:Carcinogens; D006571:Heterocyclic Compounds; D007527:Isoenzymes; D012333:RNA, Messenger; D015239:Arylsulfotransferase