Developmental aspects of hepatic heme biosynthetic capability and hematotoxicity—II. Studies on uroporphyrinogen decarboxylase

Woods, James S.; Kardish, R.

doi:10.1016/0006-2952(83)90655-x

Cited by 18 publications

(5 citation statements)

References 24 publications

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“…One possible explanation may be the consequence of accelerated hepatic heme biosynthesis that occurs during the period of perinatal development (Woods 1976). In this respect, formation of precoproporphyrin would be consistent with the observation that the specific activity of hepatic uroporphyrinogen decarboxylase in perinatal rat liver greatly exceeds that of the adult (Woods and Kardish 1983), likely generating comparably greater amounts of pentacarboxylporphyrinogen to compete with coproporphyrinogen as a substrate for coproporphyrinogen oxidase, as proposed in the etiology of precoproporphyrin in the presence of Hg exposure in adults (Woods et al 2005). Further research is required to confirm this prospect.…”

Section: Discussionsupporting

confidence: 85%

Urinary Porphyrin Excretion in Neurotypical and Autistic Children

Woods

Armel

Fulton

et al. 2010

Environ Health Perspect

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BackgroundIncreased urinary concentrations of pentacarboxyl-, precopro- and copro-porphyrins have been associated with prolonged mercury (Hg) exposure in adults, and comparable increases have been attributed to Hg exposure in children with autism (AU).ObjectivesThis study was designed to measure and compare urinary porphyrin concentrations in neurotypical (NT) children and same-age children with autism, and to examine the association between porphyrin levels and past or current Hg exposure in children with autism.MethodsThis exploratory study enrolled 278 children 2–12 years of age. We evaluated three groups: AU, pervasive developmental disorder-not otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided information at enrollment regarding medical, dental, and dietary exposures. Urine samples from all children were acquired for analyses of porphyrin, creatinine, and Hg. Differences between groups for mean porphyrin and Hg levels were evaluated. Logistic regression analysis was conducted to determine whether porphyrin levels were associated with increased risk of autism.ResultsMean urinary porphyrin concentrations are naturally high in young children and decline by as much as 2.5-fold between 2 and 12 years of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01) and pentacarboxyl- (p < 0.001) porphyrin concentrations were significantly associated with AU but not with PDD-NOS. No differences were found between NT and AU in urinary Hg levels or in past Hg exposure as determined by fish consumption, number of dental amalgam fillings, or vaccines received.ConclusionsThese findings identify disordered porphyrin metabolism as a salient characteristic of autism. Hg exposures were comparable between diagnostic groups, and a porphyrin pattern consistent with that seen in Hg-exposed adults was not apparent.

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Section: Discussionsupporting

confidence: 85%

Urinary Porphyrin Excretion in Neurotypical and Autistic Children

Woods

Armel

Fulton

et al. 2010

Environ Health Perspect

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“…Both in experimental animals and in humans exposed to heavy metals, elevated levels of porphyrins are found in the urine (Bowers et al, 1992;Woods, 1996). The steps in the heme pathway most vulnerable to heavy metal inhibition are those in which uroporphyrin decarboxylase (UROD) (Woods & Kardish, 1983) and coproporphyrinogen oxidase (CPOX) (Woods et al, 2005) are involved. The result of these inhibitions is specific elevations of cP and pentacarboxyporphyrin (5cxP) in the urine.…”

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confidence: 96%

A Prospective Study of Mercury Toxicity Biomarkers in Autistic Spectrum Disorders∗

Geier¹,

Geier²

2007

Journal of Toxicology and Environmental Health, Part A

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Porphyrins are derivatives formed in the heme synthesis pathway and porphyrins afford a measure of xenobiotic exposure. The steps in the heme pathway most vulnerable to heavy metal inhibition are uroporphyrin decarboxylase (UROD) and coproporphyrinogen oxidase (CPOX) reactions. Mercury toxicity was associated with elevations in urinary coproporphyrin (cP), pentacarboxyporphyrin (5cxP), and precoproporphyrin (prcP) (also known as keto-isocoproporphyrin) levels. Two cohorts of autistic patients in the United States and France had urine porphyrin levels associated with mercury toxicity. A prospective study of urinary porphyrin testing at LabCorp (United States) and the Laboratoire Philippe Auguste (France) involving 71 autism spectrum disorder (ASD) patients, neurotypical sibling controls, and general population controls was undertaken. ASD patients had significant elevations in urinary levels of cP, 5cxP, and prcP relative to controls, and > 50% of ASD patients had urinary cP levels more than 2 standard deviations above the mean values for neurotypical sibling controls. Significant reductions in urinary 5cxP and cP levels were observed in ASD patients following chelation. A significant correlation was found between urinary porphyrins measured at LabCorp and those measured at the Laboratoire Philippe Auguste on individual ASD patients. The established developmental neurotoxicity attributed to mercury and biochemical/genomic evidence for mercury susceptibility/toxicity in ASDs indicates a causal role for mercury. Urinary porphyrin testing is clinically available, relatively inexpensive, and noninvasive. Porphyrins need to be routinely measured in ASDs to establish if mercury toxicity is a causative factor and to evaluate the effectiveness of chelation therapy.

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“…The steps in the heme pathway most vulnerable to heavy metal inhibition are those that involve uroporphyrin decarboxylase (Woods & Kardish, 1983) and coproporphyrinogen oxidase (Woods et al, 2005). The result of these inhibitions is specific elevations of urinary coproporphyrin and pentacarboxyporphyrin levels.…”

mentioning

confidence: 98%

An Investigation of Porphyrinuria in Australian Children with Autism

Austin

Shandley

2008

Journal of Toxicology and Environmental Health, Part A

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Two recent studies, from France (Nataf et al., 2006) and the United States (Geier & Geier, 2007), identified atypical urinary porphyrin profiles in children with an autism spectrum disorder (ASD). These profiles serve as an indirect measure of environmental toxicity generally, and mercury (Hg) toxicity specifically, with the latter being a variable proposed as a causal mechanism of ASD (Bernard et al., 2001; Mutter et al., 2005). To examine whether this phenomenon occurred in a sample of Australian children with ASD, an analysis of urinary porphyrin profiles was conducted. A consistent trend in abnormal porphyrin levels was evidenced when data was compared with those previously reported in the literature. The results are suggestive of environmental toxic exposure impairing heme synthesis. Three independent studies from three continents have now demonstrated that porphyrinuria is concomitant with ASD, and that Hg may be a likely xenobiotic to produce porphyrin profiles of this nature.

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Developmental aspects of hepatic heme biosynthetic capability and hematotoxicity—II. Studies on uroporphyrinogen decarboxylase

Cited by 18 publications

References 24 publications

Urinary Porphyrin Excretion in Neurotypical and Autistic Children

Urinary Porphyrin Excretion in Neurotypical and Autistic Children

A Prospective Study of Mercury Toxicity Biomarkers in Autistic Spectrum Disorders∗

An Investigation of Porphyrinuria in Australian Children with Autism

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