VACCINE

Toxicology And Applied Pharmacology • August 2005
The association between
genetic polymorphisms of coproporphyrinogen oxidase
and an atypical porphyrinogenic response
to mercury exposure in humans
Author information
Woods JS1, Echeverria D, Heyer NJ,
Simmonds PL, Wilkerson J, Farin FM.
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
Abstract
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 excess 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.
“This finding represents
the first report of a polymorphism
in a human gene that modifies the effect of ethyl mercury
on a biological process. The atypical porphyrinogenic
response might serve as a biomarker of both mercury
exposure and susceptibility to mercury toxicity.”
http://www.ncbi.nlm.nih.gov/pubmed/?term=15967199