The association between genetic polymorphisms of coproporphyrinogen oxidase and an atypical porphyrinogenic response to mercury exposure in humans.
Previous studies have demonstrated highly specific urinary porphyrin profile (UPP) changes in response to mercury (Hg) exposure in animals and human subjects and have defined the biochemical etiology of this effect as selective alteration of the heme pathway enzymes, uroporphyrinogen decarboxylase (UROD), and coproporphyrinogen oxidase (CPOX) by Hg in the kidney. Ongoing validation studies in a population of dental practitioners with low-level occupational Hg exposure have demonstrated the predicted UPP change among approximately 85% of subjects. This study focused on the genetic etiology of an atypical porphyrinogenic response (APR) seen among the remaining 15% of Hg-exposed subjects, characterized by excess excretion of 4- and 5-carboxyl porphyrins and also of the atypical ketoisocoproporphyrin (KICP). Automated DNA-sequencing-based assays were developed to examine the 7 exons and flanking intron-exon boundaries of the CPOX gene. Among several polymorphisms identified, an A814C variant in exon 4 encoding a N272H substitution was found to be predominant among subjects with the APR. Studies suggest that this variant CPOX preferentially converts the upstream 5-carboxylporphyrin (5-CP) to KICP. By partially inhibiting the 5- to 4-decarboxylation step of UROD, Hg promotes 5-CP accumulation, accounting for e xcess KICP excretion and the APR in Hg-exposed subjects carrying the variant CPOX gene. This finding represents the first report of a polymorphism in a human gene that modifies the effect of Hg on a biological process. The APR might serve as a biomarker of both Hg exposure and susceptibility to Hg toxicity.
Woods
James S
JS
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98101, USA; Battelle Centers for Public Health Research and Evaluation, Seattle, WA 98105, USA. jwoods@u.washington.edu
Echeverria
Diana
D
Heyer
Nicholas J
NJ
Simmonds
P Lynne
PL
Wilkerson
Jasmine
J
Farin
Federico M
FM
D003304:Coproporphyrinogen Oxidase / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008628:Mercury / Q000633:toxicity*; D011110:Polymorphism, Genetic; D011166:Porphyrins / Q000652:urine*; D014575:Uroporphyrinogen Decarboxylase / Q000235:genetics
D011166:Porphyrins; D003304:Coproporphyrinogen Oxidase; D014575:Uroporphyrinogen Decarboxylase; D008628:Mercury