OBJECTIVES We sought to identify metabolic pathways characterizing human heart failure (HF) using ¹NMR based urinary metabolomic analysis in conjunction with multivariate statistics. DESIGN AND METHODS Patients with systolic HF of ischemic origin (n=15) and healthy controls (n=20) participated in this study. Patients with type 2 diabetes mellitus were excluded. RESULTS The results showed that the urine of the HF patients had higher levels of metabolites for acetate (p<0.05) and acetone (p<0.01) compared to the healthy controls. In addition, there was a perturbation in methylmalonate metabolism as shown by increased urinary levels of methylmalonic acid (p<0.001) in the HF patients. HF patients also had increased urinary levels of cytosine (p<0.01) and phenylacetylglycine (p<0.01) and decreased 1-methylnicotinamide (p<0.05) compared to healthy controls. CONCLUSIONS TCA cycle metabolites and fatty acid metabolism were modified in the HF patients, indicating altered energy metabolism. Moreover, perturbations of metabolism in nucleotide and methylmalonate were observed.

The study attempted to determine whether the growth needs of young mothers compete with the growth needs of their fetuses for available nutrients. In a large prospective study, 10- to 16-year-old mothers had significant smaller newborns at term than older mothers when the various maternal age groups were matched for prepregnancy body size and pregnancy weight gain. Five percent of the urines of 10- to 14-year-old mothers had 2+ or greater acetone vs only 2% of the urines of 17- to 32-year-old mothers (P less than .001). Acetonuria has been shown to be a marker for high perinatal mortality in undernourished gestations, and it correlated with a high perinatal mortality in the present study. The growth retardation found in the newborns of very young mothers disappeared during childhood.

Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of the oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-kappaB and activation of protein kinase C occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.

Recent studies have demonstrated that both chromium (VI) and cadmium (II) induce an oxidative stress, as determined by increased hepatic lipid peroxidation, hepatic glutathione depletion, hepatic nuclear DNA damage, and excretion of urinary lipid metabolites. However, whether chronic exposure to low levels of Cr(VI) and Cd(II) will produce an oxidative stress is not shown. The effects of oral, low (0.05 LD50) doses of sodium dichromate [Cr(VI); 2.5 mg/kg/d] and cadmium chloride [Cd(II); 4.4 mg/kg/d] in water on hepatic and brain mitochondrial and microsomal lipid peroxidation, excretion of urinary lipid metabolites including malondialdehyde, formaldehyde, acetaldehyde and acetone, and hepatic nuclear DNA-single strand breaks (SSB) were examined in female Sprague-Dawley rats over a period of 120 d. The animals were treated daily using an intragastric feeding needle. Maximum increases in hepatic and brain lipid peroxidation were observed between 60 and 75 d of treatment with both cations. Following Cr(VI) administration for 75 d, maximum increases in the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone were 2.1-, 1.8-, 2.1-, and 2.1-fold, respectively, while under the same conditions involving Cd(II) administration approximately 1.8-, 1.5-, 1.9-, and 1.5-fold increases were observed, respectively, as compared to control values. Following administration of Cr(VI) and Cd(II) for 75 d, approximately 2.4- and 3.8-fold increases in hepatic nuclear DNA-SSB were observed, respectively, while approximately 1.3- and 2.0-fold increases in brain nuclear DNA-SSB were observed, respectively. The results clearly indicate that low dose chronic administration of sodium dichromate and cadmium chloride induces an oxidative stress resulting in tissue damaging effects that may contribute to the toxicity and carcinogenicity of these two cations.

The metabolism of acetone was studied in lean and obese humans during starvation ketosis. Acetone concentrations in plasma, urine, and breath; and rates of endogenous production, elimination in breath and urine, and in vivo metabolism were determined. There was a direct relationship between plasma acetone turnover (20-77 mumol/m(2) per min) and concentration (0.19-1.68 mM). Breath and urinary excretion of acetone accounted for a 2-30% of the endogenous production rate, and in vivo metabolism accounted for the remainder. Plasma acetone oxidation accounted for congruent with60% of the production rate in 3-d fasted subjects and about 25% of the production rate in 21-d fasted subjects. About 1-2% of the total CO(2) production was derived from plasma acetone oxidation and was not related to the plasma concentration or production rate. Radioactivity from [(14)C]acetone was not detected in plasma free fatty acids, acetoacetate, beta-hydroxybutyrate, or other anionic compounds, but was present in plasma glucose, lipids, and proteins. If glucose synthesis from acetone is possible in humans, this process could account for 11% of the glucose production rate and 59% of the acetone production rate in 21-d fasted subjects. During maximum acetonemia, acetone production from acetoacetate could account for 37% of the anticipated acetoacetate production, which implies that a significant fraction of the latter compound does not undergo immediate terminal oxidation.

The presence and the importance of acetone and its metabolism in diabetic ketoacidosis has largely been ignored. Therefore, we studied acetone metabolism in nine diabetic patients in moderate to severe ketoacidosis. The concentration of acetone in plasma, urine, and breath, and the rates of acetone production and elimination in breath and urine were determined and the rates of vivo metabolism were calculated. Plasma acetone concentrations (1.55-8.91 mM) were directly related and were generally greater than acetoacetate concentrations (1.16-6.08 mM). The rates of acetone production ranged from 68 to 581 mumol/min/1.73 m2, indicating the heterogeneous nature of the patients studied. The average acetone production rate was 265 mumol/min/1.73 m2 and accounted for about 52% of the estimated acetoacetate production rate. Urinary excretion of acetone remained constant and accounted for about 7% of the acetone production rate in all patients. There was a positive linear relationship between the percentage of the acetone production rate accounted for by excretion in breath and the plasma acetone concentration. At low plasma acetone concentrations, approximately 20%, and at high plasma acetone concentrations, approximately 80% of the production rate was accounted for by breath acetone. In contrast, there was a negative linear relationship between the percentage of acetone production rate undergoing in vivo metabolism and plasma acetone concentration. At low plasma acetone concentrations, approximately 75%, and at high concentrations, approximately 20% of acetone production rate was accounted for by in vivo metabolism. Radioactivity from 2-[14C]-acetone was variably present in plasma acetone, glucose, lipids and proteins. No radioactivity was found in plasma acetoacetate, beta-hydroxy butyrate or free fatty acids or other anionic compounds. Exchange rates of acetone into other metabolites could not be estimated because of non-steady-state precursor product relationships in these patients.

A prospective study of infants born to women with diabetes mellitus is reported. The children were examined at birth and followed at 1, 3, and 5 years of age. Medical and psychological information was obtained through follow-up examinations. Intrauterine growth was atypical and there was an increase in neonatal problems and congenital malformations. There was an increased incidence of intellectual delay at 3 and 5 years of age. The presence of acetone in the urine during pregnancy had a significant, adverse effect on intellectual status of the offspring at 5 years of age. Birth weight was negatively related to intellectual status at both 3 and 5 years of age.

The study was undertaken to determine the causes of the more frequent pre-term deliveries, fetal and neonatal deaths associated with maternal urinary-tract infections during pregnancy. The combined perinatal mortality rate for eight common placental and fetal disorders was 42 per thousand births in the infected vs. 21 per thousand in the noninfected, owing to a greater mortality from noninfectious placental and fetal disorders in the gestations with the urinary-tract infections (P less than 0.001). All the mortality excess took place when the urinary-tract infections occurred within 15 days of delivery. Death rates were highest when the urinary-tract infections coexisted with maternal hypertension and acetonuria.Hydramnios, amniotic-fluid bacterial infections and abruptio placentae were responsible for two thirds of the more frequent preterm deliveries in the pregnancies complicated by urinary-tract infections.

Formaldehyde (FA), acetaldehyde (ACT), malondialdehyde (MDA) and acetone (ACON) were simultaneously identified in urine, and their excretion quantitated in response to chemically induced oxidative stress. Urine samples of female Sprague-Dawley rats were collected over dry ice and derivatized with 2,4-dinitrophenylhydrazine. The hydrazones of the four lipid metabolic products were quantitated by high-performance liquid chromatography on a Waters 10-microns mu-Bondapak C18 column. The identities of FA, ACT, MDA and ACON in urine were confirmed by gas chromatography-mass spectrometry. An oxidative stress was induced by orally administering 100 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin, 75 mg/kg paraquat, 6 mg/kg endrin or 2.5 ml/kg carbon tetrachloride to rats. Urinary excretion of FA, ACT, MDA and ACON increased relative to control animals 24 h after treatment with all xenobiotics. The system has wide-spread applicability to the investigation of altered lipid metabolism in disease states and exposure to environmental pollutants.