NDT Advance Access originally published online on July 27, 2004
Nephrology Dialysis Transplantation 2004 19(10):2576-2583; doi:10.1093/ndt/gfh425
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Nephrol Dial Transplant Vol. 19 No. 10 © ERA-EDTA 2004; all rights reserved
Original Article
4-Heptanone is a metabolite of the plasticizer di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients
1 Department of Clinical Chemistry and Molecular Diagnostics, Klinikum der Philipps-Universität Marburg, Marburg, 2 Department of Endocrinology, Metabolism and Clinical Chemistry, 3 Institute of Occupational and Social Medicine, and 4 Department of Nephrology, Internal Medicine Universitätsklinikum Tübingen, Tübingen, Germany
Correspondence and offprint requests to: Dr. Dr Hans Günther Wahl, Klinikum der Philipps-Universität Marburg, Department of Clinical Chemistry and Molecular Diagnostics, D-35033 Marburg, Germany. Email: hg.wahl{at}med.uni-marburg.de
Background. There is an ongoing discussion about the risks of di(2-ethylhexyl) phthalate (DEHP) exposure for the general population as well as for specific subgroups in various medical settings. Haemodialysis patients certainly belong to the group with the highest exposure taking into account the repeated treatments over a long period of time. Many studies have shown that DEHP metabolites are more active with regard to cellular responses than DEHP itself. Although 4-heptanone has been shown to be a DEHP metabolite in rats, this has never been tested in humans. On the other hand, 4-heptanone was reported to be associated with diabetes mellitus.
Methods. After establishing analytical methods for all postulated metabolites, we analysed (i) plasma samples from 50 patients on haemodialysis and 50 controls; (ii) urine samples from 100 diabetic patients and 100 controls; and (iii) urine samples from 10 controls receiving DEHP intravenously.
Results. 4-Heptanone concentrations in urine did not differ between controls (128.6±11.4 µg/l, mean± SEM) and diabetic patients (131.2±11.6 µg/l) but were significantly elevated in plasma from haemodialysis patients (95.9±9.6 µg/l) compared with controls (10.4±0.5 µg/l). Exposure to DEHP led to a significant increase (P<0.001) of the metabolite 4-heptanone and all the proposed intermediates in urine of healthy persons within 24 h.
Conclusions. These studies show that 4-heptanone is not associated with diabetes but is a major DEHP metabolite in humans. Studies concerning the toxicity of DEHP in haemodialysis patients and other highly exposed groups should therefore include 4-heptanone together with DEHP and its primary metabolites mono(2-ethylhexyl) phthalate (MEHP) and 2-ethylhexanol.
Keywords: DEHP; diabetes mellitus; haemodialysis; 4-heptanone; in vivo metabolism