Frequency distribution of phenol sulfotransferase 1A1 activity in platelet cells from healthy Japanese subjects.
OBJECTIVE
To determine the distribution of sulfotransferase 1A1 (SULT1A1) activities, we used trans-4-hydroxytamoxifen (OHT) as a substrate to test samples from a Japanese population to examine whether the SULT1A1*2 allele can account for the wide distribution of OHT sulfating activity. We also studied genetic mutations other than the SULT1A1*2 allele to determine the cause of differences in SULT1A1 protein expression and activity.


METHODS
The subjects were 103 healthy Japanese adults. Identification of SULT1A1 genotypes was performed using a polymerase chain reaction-restriction fragment length polymorphism method. SULT1A1 activity in platelet cytosol was assayed using OHT as a substrate. SULT1A1 protein was detected using Western blotting analysis. Mutations other than SULT1A1*2 in the SULT1A1 gene were detected using sequencing analysis.


RESULTS
SULT1A1*2 allele frequency was found to be 16.5%, while SULT1A1 activity ranged from 63 to 1860pmol sulfated/h/mg platelet protein (260+/-241pmol sulfated/h/mg platelet protein, median+/-S.D.) using OHT as a substrate. The median values in subjects with SULT*1/*2 (221+/-113pmol sulfated/h/mg platelet protein, range 63-442, n=26) and SULT*2/*2 (124+/-66pmol sulfated/h/mg platelet protein, range 74-231, n=4) were significantly lower than that in subjects with SULT*1/*1 (303+/-267pmol sulfated/h/mg platelet protein, range 97-1859, n=73). A novel G148C mutation was found in one subject, who showed the lowest OHT sulfating activity, for a frequency of 0.49%.


CONCLUSIONS
There was wide variety of OHT sulfating activities found among the present healthy Japanese subjects. The SULT1A1*2 allele was found to be a common variant allele and was associated with decreased OHT sulfating activity. These observations may be related to inter-individual variations of OHT pharmacokinetics and the pharmacologic effects of tamoxifen seen in Japanese patients with breast cancer.
Ohtake
Eiko
E
Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, Tokyo, Japan.
Kakihara
Fumiko
F
Matsumoto
Naoko
N
Ozawa
Shogo
S
Ohno
Yasuo
Y
Hasegawa
Setsuo
S
Suzuki
Hiroshi
H
Kubota
Takahiro
T
D000328:Adult; D000368:Aged; D015239:Arylsulfotransferase / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism
D013629:Tamoxifen; C016601:afimoxifene; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human