Urinary bisphenol-A levels in children with type 1 diabetes mellitus.

BACKGROUND: Bisphenol-A (BPA) is one of the most abundantly produced chemicals globally. Concerns have been raised about BPA's possible role in the pathogenesis of type 1 diabetes mellitus (T1DM). The main aim of the current study was to evaluate the possible association between BPA exposure and T1DM. The second aim was to investigate children's possible BPA exposure routes in Turkey. METHODS: A total of 100 children aged between 5 and 18 years including 50 children with T1DM and 50 healthy children were included. Urinary BPA levels of all children were measured using high-performance liquid chromatography. Mothers of children enrolled in the study were also requested to complete a survey that included questions on the sociodemographic characteristics, medical history and possible BPA exposure routes of their children. RESULTS: In the T1DM group, urinary BPA levels were slightly higher compared to the control group, but this difference was not significant (p=0.510). However, there was an inverse relationship between current urinary BPA levels and birth weight. It was found that the use of plastic kettles and the consumption of dairy products in plastic boxes significantly increased the urinary BPA concentrations in all subjects. CONCLUSIONS: Although there was no significant association between urinary BPA levels and T1DM, we found an inverse relationship between current urinary BPA levels and birth weight. This finding might be important for prenatal exposure, and further prospective research must be conducted. Also, the use of plastic kettles, which has not been mentioned much in the literature before, was found to be an important exposure route for BPA.

Urinary bisphenol A concentration and the risk of central obesity in Chinese adults: A prospective study.

BACKGROUND: Bisphenol A (BPA) exposure has been associated with diabetes and related metabolic disorders, such as obesity, but studies of the association of urinary BPA concentrations with central obesity risk are limited. The aim of this study was to prospectively investigate the association between urinary BPA and incident central obesity in a Chinese population aged ≥40 years. METHODS: The study followed 888 participants from Shanghai, China, who did not have central obesity at baseline (in 2009) for 4 years. Concentrations of BPA were measured in baseline morning spot urine samples. Central obesity was defined as waist circumference ≥90 cm in men and ≥80 cm in women. RESULTS: During a mean follow-up of 4 years, 124 (14.0%) participants developed central obesity. Each 1-unit increase in log [BPA] was positively associated with a 2.30-fold risk of incident central obesity (95% confidence interval [CI] 1.39-3.78; P < 0.001) after adjustment for confounders. Compared with the lowest tertile of urinary BPA concentration, Tertiles 2 and 3 were associated with a higher risk of incident central obesity (odds ratios 1.73 [95% CI 1.04-2.88] and 1.81 [95% CI 1.08-3.05], respectively). Stratified analysis showed significant associations of BPA with incident central obesity in women and individuals <60 years of age, with normal weight, non-smokers, non-drinkers, or non-hypertensives. CONCLUSIONS: The results indicate that higher urinary BPA concentrations may be associated with a greater risk of incident central obesity in Chinese adults. The study emphasizes the effects of BPA exposure on metabolic risk from a public health perspective.

Pharmacokinetics, tissue distribution and excretion of manganese (III) meso-tetra [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, a novel superoxide dismutase mimic, in Wistar rats.

Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel superoxide dismutase mimic. It exhibits strong free-radical scavenging activities in vitro and in vivo. The aim of the present study was to investigate the pharmacokinetics, tissue distribution and excretion of HSJ-0017 in Wistar rats following a single intravenous administration. Wistar rats were given different doses of HSJ-0017 by single intravenous injection. Biological samples of rats were collected and were assayed by the HPLC method. The pharmacokinetics, tissue distribution and excretion of HSJ-0017 were investigated. The pharmacokinetic data of HSJ-0017 in rats following intravenous injection was best-fit by a two-compartment model. T max of HSJ-0017 in plasma following intravenous injection was 0.083 h. AUC and plasma drug concentration were found to increase in a dose-related fashion. The highest concentrations of HSJ-0017 were detected in the liver (82.25 ± 13.99 µg/g) of rats, followed by the kidney, small intestine, lung, plasma, heart, spleen, and stomach within 2 h postdose. No HSJ-0017 was detected in the uterus, parorchis or brain of rats during the 24-h period of examination. The total cumulative excretion of HSJ-0017 in rat bile and urine were found to be 78.85 and 67.58 %, respectively. Our study has led to the view that the HSJ-0017 can be rapidly distributed to tissues after intravenous administration, but cannot diffuse through the blood-brain barrier. The faecal and biliary excretion of unchanged HSJ-0017 are the major routes of HSJ-0017 elimination.

Erythritol is a sweet antioxidant.

OBJECTIVE: Hyperglycemia, oxidative stress, and the onset and progression of diabetic complications are strongly linked. Reduction of oxidative stress could be of utmost importance in the long-term treatment of diabetic patients. The chronic nature of the disease calls for a mode of antioxidant intake that can be sustained easily, e.g., by the diet. Erythritol, a simple polyol, could be such a compound. It is orally available, well tolerated, and its chemical structure resembles that of mannitol, a well-known hydroxyl radical (HO*) scavenger. METHODS: We studied the antioxidant properties of erythritol in vitro and subsequently determined its antioxidant activity and its vasoprotective effect in the streptozotocin diabetic rat. RESULTS: Erythritol was shown to be an excellent HO* radical scavenger and an inhibitor of 2,2'-azobis-2-amidinopropane dihydrochloride-induced hemolysis but inert toward superoxide radicals. High-performance liquid chromatographic and electron spin resonance spectroscopy studies showed that the reaction of erythritol with hydroxyl radicals resulted in the formation of erythrose and erythrulose by abstraction of a carbon-bound hydrogen atom. In the streptozotocin diabetic rat, erythritol displayed an endothelium-protective effect and, in accordance with the in vitro experiments, erythrose was found in the urine of erythritol-consuming rats. CONCLUSION: Erythritol acts as an antioxidant in vivo and may help protect against hyperglycemia-induced vascular damage.

Evaluation of the role of breast cancer resistance protein (BCRP/ABCG2) and multidrug resistance-associated protein 4 (MRP4/ABCC4) in the urinary excretion of sulfate and glucuronide metabolites of edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one).

Edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. Edaravone is mainly excreted into the urine after conjugation to glucuronide or sulfate. Previous studies have demonstrated that edaravone sulfate is a good substrate of human organic anion transporter (OAT) 1 (SLC22A6) and human OAT3 (SLC22A8). In this study, we examined the involvement of breast cancer resistance protein [BCRP (ABCG2)] and [multidrug resistance-associated protein 4 MRP4 (ABCC4)] in the luminal efflux in the kidney. Increased ATP-dependent uptake of edaravone sulfate but not edaravone glucuronide was observed in BCRP-expressing membrane vesicles compared with control vesicles (Km = 16.5 microM). In contrast, edaravone glucuronide, but not edaravone sulfate, exhibited greater ATP-dependent uptake in MRP4-expressing membrane vesicles than that in control vesicles (Km = 9.85 microM). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of edaravone glucuronide by MRP4. The functional importance of BCRP and MRP4 in the urinary excretion of edaravone sulfate and edaravone glucuronide, respectively, was investigated using Bcrp and Mrp4 knockout mice. The renal clearance with respect to the kidney concentration of edaravone sulfate was reduced significantly but not abolished in Bcrp knockout mice compared with wild-type mice (3.62 versus 4.85 ml/min/kg b.wt.). The renal clearance of edaravone glucuronide was lower in Mrp4 knockout mice than wild-type mice (2.01 versus 5.06 ml/min/kg BW). Our results suggest that Bcrp and Mrp4 are partly involved in the luminal efflux of edaravone sulfate and edaravone glucuronide, respectively.

Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke.

OBJECTIVE: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment. METHODS: Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 micro mol/l for subjects with mild (GFR 50-100 ml/min) and moderate (GFR 30-49 ml/min) renal impairment, and 30 micro mol/l for subjects with severe renal impairment (GFR <30 ml/min). GFR was measured as sinistrin clearance. RESULTS: The data indicated no tolerability or safety concerns with NXY-059. The half-life, which normally is approximately 2-4 h, was in the order of 10-12 h in subjects with moderate and severe renal impairment. The distribution parameters steady-state volume of distribution (V(ss)) and unbound fraction in plasma at 13-15 l and 0.53-0.58, respectively, were virtually the same as previously observed in healthy subjects. Plasma clearance of NXY-059, which ranged from 9 ml/min to 76 ml/min, was directly proportional to kidney function (GFR) with no discernible contribution by non-renal clearance. The correlation coefficient squared (r(2)) was 0.93, both when the renal function parameter was GFR and when it was creatinine clearance estimated from serum creatinine, age, weight and sex. CONCLUSION: Non-renal elimination of NXY-059 appeared to be insignificant even in subjects with low renal capacity. Patients with renal impairment should have their dose of NXY-059 adjusted for renal function, conveniently assessed from serum creatinine.

Polymorphism of xenobiotic-metabolizing enzymes and excretion of styrene-specific mercapturic acids.

The role of polymorphic xenobiotic-metabolizing enzymes in the interindividual variability of phenylhydroxyethyl mercapturic acids (PHEMAs) was investigated in 56 styrene-exposed workers. Ambient monitoring was carried out using passive personal samplers (geometric mean, 157 mg/m3 8-h time-weighted average; geometric standard deviation, 2.90). Biomonitoring was based on mandelic acid and phenylglyoxylic acid in urine spot samples collected at the end of the work shift ("end-of-shift") and prior to the subsequent shift ("next morning"). Four PHEMA diastereoisomers, namely (R,R)-M1, (S,R)-M1, (S,R)-M2, and (R,R)-M2, were determined by HPLC/tandem mass spectrometry. The genotypes of glutathione S-transferases M1-1 (GSTM1), T1-1 (GSTT1) and P1-1 (GSTP1), and microsomal epoxide hydrolase (EPHX) were characterized by PCR-based methods. Workers bearing the GSTM1pos genotype showed PHEMA concentrations five and six times higher (in end-of-shift and next-morning samples, respectively) as compared to GSTM1null people. In GSTM1pos subjects, (R,R)-M1 was the main mercapturate affected by the GSTM1 status, accounting for 54 and 68% of total PHEMAs in end-of-shift and next-morning samples, respectively. Compared to GSTM1null, GSTM1pos subjects excreted more -M1 than -M2 and more (R,R)-M1 and (S,R)-M2 than (S,R)-M1 and (R,R)-M2 diastereoisomers. Thus, GSTM1-1 is the main isoenzyme catalyzing GSH-conjugation of styrene-7,8-oxide in humans and it seems to act in a regio- and stereoselective way. PHEMAs cannot be recommended as biomarkers of exposure to styrene, unless the GSTM1 genotype is considered in data interpretation. Their role as biomarkers of susceptibility deserves further studies.

Urinary metabolites of gallic acid in rats and their radical-scavenging effects on 1,1-diphenyl-2-picrylhydrazyl radical.

As a part of our studies on the metabolism of natural compounds, gallic acid was orally administered to rats. The urinary metabolites were analyzed by high-performance liquid chromatography, and their structures were determined to be pyrogallol (M1), pyrogallol-1-O-beta-D-glucuronide (M2), 4-O-methylgallic acid-3-O-sulfate (M3), 2-O-methylpyrogallol-1-O-beta-D-glucuronide (M4), 2-O-methylpyrogallol (M5), 4-O-methylgallic acid (M6), and unchanged gallic acid on the basis of chemical and spectral data. The radical scavenging effects of gallic acid and its urinary metabolites were evaluated using 1,1-diphenyl-2-picrylhydrazyl radical.

Absorption of ferulic acid from low-alcohol beer.

Flavonoids and monophenolic compounds have been well-described over recent years for their properties as antioxidants and scavengers of reactive oxygen and nitrogen species. A number of epidemiological studies implicate a role for flavonoids in reducing the risk of coronary heart disease. In particular, the focus has been on flavonol-rich fruit and vegetables and flavonoid-rich beverages, especially tea and red wine. Mechanisms of protection are unclear since the absorption, distribution, metabolism and elimination of dietary phenolics have not yet been extensively investigated. Here we report the bioavailability of ferulic acid, 4-hydroxy-3-methoxy-cinnamic acid, the major hydroxycinnamate in beer. Studies of the pharmacokinetics of urinary excretion of ferulic acid from low alcohol beer consumption in humans have been undertaken. The results show that ferulic acid is absorbed with a peak time for maximal excretion of ca. 8 h and the mean cumulative amount excreted is 5.8 +/- 3.2 mg. These findings are consistent with the uptake of ferulic acid from dietary sources, such as tomatoes, and suggest that ferulic acid is more bioavailable than individual dietary flavonoids and phenolics so far studied.

N -Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion.

A decrease of plasma homocysteine (Hcy) may represent a therapeutic promise for reducing the impact of atherosclerosis. N -Acetyl-cysteine (NAC) is a thiol-containing compound interfering with endogenous thiols, cysteine (Cys) and Hcy, by forming with them mixed disulphides with a possibly more efficient renal clearance. The aim of this work was to assess the effect of NAC intravenous infusion on plasma levels of different forms of Hcy and particularly to verify the effect on Hcy renal excretion. We collected basal blood samples at 0.5, 1, 2, 5, 8 and 24 h after the beginning of NAC infusion (50 mg kg(-1)body wt.) and also 24-h urine samples of the day of NAC infusion and of the day before and of the day after the infusion in ten healthy subjects (mean age 73+/-15). Urinary and plasma thiols (Hcy, Cys and NAC) were assayed by HPLC. Both total plasma Hcy (approx. 69%vs basal values) and Cys (approx. 40%vs basal values) fell progressively, reaching a minimum 5 h after infusion start; total free (i.e. not bound to proteins) Hcy (2.2+/-1.8 down from 4.4+/-4.2 nmol ml(-1)) and Cys (70.4+/-39.8 down from 113. 3+/-61.2 nmol ml(-1)) decreased as well. Reduced (thiolic-free form) Hcy and Cys decreased during infusion, though not as pronounced as for the other forms. Percentagewise, out of the total plasma levels, Hcy and Cys total free form and reduced form tended to increase over infusion as well as their difference (i.e. the plasma mixed disulphide moiety), thus supporting the idea that excess NAC displaces thiols from their plasma binding sites forming mixed disulphides. Urinary total Cys and Hcy excretion significantly increased at the end of the day of NAC infusion (tenfold for Cys and fivefold for Hcy) and reduced appreciably on the following day. Also urinary excretion of the free form of Cys and Hcy increased at the end of the day of NAC infusion, although in a lower amount with respect of total amounts, meaning a reduction of percentage Cys and Hcy excreted as the free form; for none of the patients had proteinuria, the 'free' form of urine thiols has to be identified in the 'reduced' form, the difference between the total and free form reflecting the 'mixed disulphide' moiety. NAC intravenous administration induces an efficient and rapid reduction of plasma thiols, particularly of Hcy; our data support the hypothesis that NAC displaces thiols from their binding protein sites and forms, in excess of plasma NAC, mixed disulphides (NAC-Hcy) with an high renal clearance. This effect may represent the start of an alternative approach in the treatment of hyperhomocysteinaemic conditions.

Comparison between subjective and actigraphic measurement of sleep and sleep rhythms.

Sleep is often assessed in circadian rhythm studies and long-term monitoring is required to detect any changes in sleep over time. The present study aims to investigate the ability of the two most commonly employed methods, actigraphy and sleep logs, to identify circadian sleep/wake disorders and measure changes in sleep patterns over time. In addition, the study assesses whether sleep measured by both methods shows the same relationship with an established circadian phase marker, urinary 6-sulphatoxymelatonin. A total of 49 registered blind subjects with different types of circadian rhythms were studied daily for at least four weeks. Grouped analysis of all study days for all subjects was performed for all sleep parameters (1062-1150 days data per sleep parameter). Good correlations were observed when comparing the measurement of sleep timing and duration (sleep onset, sleep offset, night sleep duration, day-time nap duration). However, the methods were poorly correlated in their assessment of transitions between sleep and wake states (sleep latency, number and duration of night awakenings, number of day-time naps). There were also large and inconsistent differences in the measurement of the absolute sleep parameters. Overall, actigraphs recorded a shorter sleep latency, advanced onset time, increased number and duration of night awakenings, delayed offset, increased night sleep duration and increased number and duration of naps compared with the subjective sleep logs. Despite this, there was good agreement between the methods for measuring changes in sleep patterns over time. In particular, the methods agreed when assessing changes in sleep in relation to a circadian phase marker (the 6-sulphatoxymelatonin (aMT6s) rhythm) in both entrained (n = 30) and free-running (n = 4) subjects.

The effect of age and sex on metabolism and urinary excretion of antipyrine.

BACKGROUND: Drug-metabolizing capacity is generally reduced in the elderly. The purpose of this investigation was to study antipyrine clearance and metabolite excretion in old subjects of both sexes. METHODS: Saliva clearance of antipyrine and the production clearances of antipyrine metabolites were studied in young and elderly volunteers of both sexes. Seventy-six elderly subjects (mean age 81 years) were compared with a group of 24 young subjects (mean age 29 years). RESULTS: After oral administration, salivary antipyrine clearance declined with age in both males and females, whether or not this variable was corrected for weight, and antipyrine half-life was significantly prolonged in elderly groups of either sex. The percentage urinary excretion of the antipyrine metabolites (hydroxymethylantipyrine, HMA; norantipyrine, NORA; and 4-hydroxyantipyrine, OHA) was reduced at 48 h in the elderly compared to young subjects by 23%, 31%, and 10%, respectively, in males, and by 41%, 41%, and 24%, respectively, in females. The formation clearance of HMA was reduced by 47% in males and by 52% in females. NORA clearance declined by 42 and 56%, respectively, in males and females. A decrease of 30% in males and 44% in females was observed in OHA clearance. CONCLUSIONS: The findings suggest that aging leads to altered disposition of antipyrine in both males and females and that the main metabolic pathways of the compound are not different in the elderly.