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Abstract
This study was conducted to assess inter-species and inter-individual differences in the metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans and mice. The activities of four DEHP-metabolizing enzymes [lipase, UDP-glucuronocyltransferase (UGT), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH)] were measured in the livers of 38 human subjects of various ages and in eight 129/Sv male mice. Microsomal lipase activity was significantly lower in humans than in mice. The V max/K m value in humans was one-seventh of that in mice, microsomal UGT activity in humans was a sixth of that in mice, and cytosolic ALDH activity for 2-ethylhexanal in humans was one-half of that in mice. In contrast, ADH activity for 2-ethylhexanol was twofold higher in humans than in mice. The total amount of DEHP urinary metabolites and the concentration of mono(2-ethylhexyl)phthalate (MEHP) were much higher in intact mice than in the U.S. general population based on data reported elsewhere, regardless of the similar estimated DEHP intake between these mice and the human reference population. However, mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) levels were higher in the latter than in the former. Of note, inter-subject variability in the activities of all enzymes measured was 10-26-fold. The inter-individual variation in the metabolism of DEHP in humans may be greater than the difference between mice and humans (inter-species variation), and both may affects the risk assessment of DEHP.
Highlights
Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer to improve the plasticity and elasticity of Environ Health Prev Med (2014) 19:117–125 polyvinyl chloride (PVC) products
The total amount of DEHP urinary metabolites and the concentration of mono(2ethylhexyl)phthalate (MEHP) were much higher in intact mice than in the U.S general population based on data reported elsewhere, regardless of the similar estimated DEHP intake between these mice and the human reference population
An aliquot (500 ll) of urine was mixed with 1110 ll of reaction mixture containing a final concentration of 45 mM acetate buffer, 60 U of b-glucuronidase [10], and 100 ng deuterated-MEHP as an internal standard and incubated at 37 °C overnight, following which the urinary metabolites of DEHP were extracted with ethyl acetate and converted to tert-butyldimethylsilyl derivatives by adding N-methyl-N-(tert-butyldimethylsilyl) trifluoroacetamide, as reported previously [5]
Summary
Di(2-ethylhexyl)phthalate (DEHP) is widely used as a plasticizer to improve the plasticity and elasticity of Environ Health Prev Med (2014) 19:117–125 polyvinyl chloride (PVC) products. These final products contain between 10 and 60 % DEHP (w/w). Once absorbed into the body, DEHP is rapidly hydrolyzed to mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) by the catalytic action of lipase [2, 3]. The remaining MEHP is excreted in the urine directly or in the conjugation form by the catalytic action of UDP-glucuronocyltransferase (UGT). 2-EH is metabolized mainly to carboxylic acid [mainly 2-ethylhexanoic acid, 2-EHA] via 2-ethylhexanal by the catalytic action of ADH and ALDH [2]. The 2-EHA formed is further oxidized to a dicarboxylic acid in a way similar to MEHP oxidation
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