4-Heptanone is a metabolite of the plasticizer di(2-ethylhexyl) phthalate (DEHP) in haemodialysis patients

Abstract

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 mg/l, mean± SEM) and diabetic patients (131.2±11.6 mg/l) but were significantly elevated in plasma from haemodialysis patients (95.9±9.6 mg/l) compared with controls (10.4±0.5 mg/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.

Breath biomarkers of liver cirrhosis

“…After manual revision of the list one of the compounds (4-heptanone) has been excluded of the analysis. 4-heptanone is a major metabolite of di (2-ethylhexyl) phthalate (DEHP), a plasticizer used in polyvinyl chloride products, not associated with insulin resistance or liver metabolism [19]. It is incorporated in many medical devices like tubing, infusion sets, and storage bags for blood, parenteral nutrition and dialysis fluids.…”

Urinary Volatile Organic Compounds as Potential Biomarkers in Idiopathic Membranous Nephropathy

“…In this study, 4-heptanone and 2-pentanone were significantly increased in iMN patients, which might indicate some relationship between oxidative stress and iMN. Since ketones were reported to be particularly abundant in human urine [22] , Wahl et al [23] have identified that 4-heptanone in urine is most probably of exogenous origin, which is supposed to be a product of β-oxidation of 2-ethylhexanoic acid, a metabolic product of the plasticizer di-(2-ethylhexyl)-phthalate. Previous studies confirmed that 4-heptanone was related to more specific stages of diabetic polyneuropathy [24] .…”

Gases as Uremic Toxins: Is There Something in the Air?

“…4-Heptanone has been described previously in the plasma of hemodialysis patients as a degradation product of diethylhexylphthalate. 38 In analogy to 4-heptanone, 4-heptanal and 2-heptanone preferentially or exclusively occurred in patients undergoing hemodialysis as well. 18 The question arises of why the analysis of exhaled VOCs has not been used as a clinical diagnostic tool thus far, although uremic fetor has long been believed to be characteristic of renal failure.…”