Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles.
Large interindividual variability in urinary arsenic profiles, following chronic inorganic arsenic exposure, is well-known in humans. To understand this variability, we studied the relationship between polymorphisms in the gene for human monomethylarsonic acid (MMA(V)) reductase/hGSTO1 and the urinary arsenic profiles of individuals chronically exposed to arsenic in their drinking water. To ensure that we did not overlook rare polymorphisms, not included in the public databases, we amplified and sequenced all six exons of the gene and their flanking regions, using DNA isolated from peripheral blood samples of 75 subjects, living in the vicinity of Torreon, Mexico. Four groups, based on the levels of arsenic (9-100 microg/L) in their drinking water, were studied. We identified six novel polymorphisms and two reported previously. The novel polymorphisms were a three base pair deletion (delGGC) in the first intron; a G > C transversion, leading to a serine-to-cysteine substitution at amino acid 86; a G > T transversion and a A > T transversion in intron 5; a G > A transition resulting in glutamate-to-lysine substitution in amino acid 208; and a C > T transition producing an alanine-to-valine substitution in amino acid 236. Two subjects displayed significant differences in patterns of urinary arsenic; they had increased levels of urinary inorganic arsenic and reduced levels of methylated urinary arsenic species as compared to the rest of the study population. These two subjects had the same unique polymorphisms in hGSTO1 in that they were heterozygous for E155del and Glu208Lys. The identified SNPs may be one of the reasons for the large interindividual variability in the response of humans to chronic inorganic arsenic exposure. The findings suggest the need for further studies to identify unambiguously specific polymorphisms that may account for interindividual variability in the human response to chronic inorganic arsenic exposure.
Marnell
Lorraine L
LL
Department of Molecular and Cellular Biology, Center for Toxicology, University of Arizona, Tucson Arizona 85721-0106, USA.
Garcia-Vargas
Gonzalo G
GG
Chowdhury
Uttam K
UK
Zakharyan
Robert A
RA
Walsh
Bruce
B
Avram
Mihaela D
MD
Kopplin
Michael J
MJ
Cebrián
Mariano E
ME
Silbergeld
Ellen K
EK
Aposhian
H Vasken
HV
D000293:Adolescent; D000328:Adult; D000368:Aged; D001151:Arsenic / Q000737:chemistry / Q000652:urine*; D001152:Arsenicals / Q000378:metabolism*; D002874:Chromosome Mapping; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
D001152:Arsenicals; D017931:DNA Primers; D005982:Glutathione Transferase; C020300:monomethylarsonic acid; D001151:Arsenic