The iatrogenic risks associated with excessive Mn administration in parenteral nutrition (PN) patients are well documented. Hypermanganesemia and neurotoxicity are associated with the duration of Mn supplementation, Mn dosage, as well as pathological conditions, such as anemia or cholestasis. Recent PN guidelines recommend the biomonitoring of patients if they receive Mn in their PN longer than 30 days. The data in the literature are conflicting about the method for assessing Mn stores in humans as a definitive biomarker of Mn exposure or induced-neurotoxicity has yet to be identified. The biomonitoring of Mn relies on the analysis of whole blood Mn (WB Mn) levels, which are highly variable among human population and are not strictly correlated with Mn-induced neurotoxicity. Alterations in dopaminergic (DAergic) and catecholaminergic metabolism have been studied as predictive biomarkers of Mn-induced neurotoxicity. Given these limitations, this review addresses various approaches for biomonitoring Mn exposure and neurotoxic risk.

Summary The increasing exposure of human populations to excessive levels of metals continues to represent a matter of public health concern. Several biomarkers have been studied and proposed for the detection of adverse health effects induced by lead (Pb), arsenic (As) and manganese (Mn); however, these studies have relied on exposures to each single metal, which fails to replicate real-life exposure scenarios. These 3 metals are commonly detected in different environmental, occupational and food contexts and they share common neurotoxic effects, which are progressive and once clinically apparent may be irreversible. Thus, chronic exposure to low levels of a mixture of these metals represents an additive risk of toxicity. Building upon their shared mechanisms of toxicity, such as oxidative stress, interference with neurotransmitters and effects on hematopoietic system, we address putative biomarkers, which may be assist in assessing onset of neurological diseases associated with exposure to this metal mixture.

Lead (Pb), arsenic (As) and manganese (Mn) are neurotoxic elements that often occur in mixtures for which practically no information is available on biomarkers (BMs) for the evaluation of exposure/effects. Exposures to these metals may increase delta-aminolevulinic acid (delta-ALA), which in itself may potentiate neurotoxicity. The objective of this study was to investigate the utility of urinary delta-ALA (delta-ALA-U) levels as BM of exposure and/or neurotoxic effects induced by this mixture. Five groups of Wistar rats were treated for 8 days with Pb (5 mg/kg), As (60 mg/L), Mn (10 mg/kg), the 3-metal mixture (same doses of the single metals), and control group. Motor activity was evaluated and 24-h urine collected before and after the treatment. 24-hours (h) after the last dose, the rats were sacrificed and the brains removed for analyses. Delta-ALA and metal levels were determined in brain and urine. Co-treated rats showed a significant (p<0.05) correlation between increased Pb, As, Mn and delta-ALA levels in the brain and decreased motor activity. Delta-ALA-U concentrations were higher in the mixture-treated group than the sum of the delta-ALA-U levels in each single-treated groups and discriminated (p<0.05) between the mixture and untreated rats. Moreover, delta-ALA-U was correlated (p<0.05) with brain delta-ALA levels. These results establish that treatments with this metal mixture exacerbate behavioral dysfunction, increasing most prominently brain Pb levels. This study is the first to establish that delta-ALA-U levels represent a sensitive BM of exposure/neurotoxic effect to this metal mixture.

HighlightsValidation process for the analysis of metals in fruit juices was implemented.Cd, Cr, Pb, As, Ni and Mn were determined in fruit juices.62% of the samples had Ni above the maximum permissible values according with the Portuguese legislation.All the samples had Mn above the Portuguese legislation limits.A reduction of metal concentration in Portuguese juices is recommended.

Abstract-Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37°C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N-and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclizationactivated prodrugs. Ó 2005 Elsevier Ltd. All rights reserved.Phenol drugs are attractive targets for prodrug design due to their extensive first-pass metabolism. 1 In the case of paracetamol, 1 (Scheme 1), the metabolism can lead to serious hepatic and renal toxic effects. 2 These toxic side-effects have been ascribed to the formation of a N-acetylquinone imine, 3 which is detoxified by reaction with glutathione leading to glutathione depletion and cell death. 3,4 Esterification of paracetamol with amino acids was reported as a means to obviate the severe hepatotoxicity of the drug at high doses 5 as well as to increase aqueous solubility. 6 We now report that dipeptides may also be used as carriers for hydroxyl-containing drugs. Dipeptide esters and amides (2, X = O or NH, Scheme 1) can deliver the parent drug through enzyme-independent processes such as the intramolecular cyclization to form the corresponding diketopiperazines (3, DKPs, Scheme 1). 7,8 The major drawback of using dipeptides as carrier candidates for prodrugs is their susceptibility to non-specific peptidases. However, enzymatically stable dipeptides (e.g., containing 2-aminoisobutyric acid or N-methylglycine as carriers) have been used successfully to improve physico-chemical properties of cytarabine 9 and cyclosporine. 10 Despite the potential of dipeptides as carriers for cyclization-activated prodrugs, there is a lack of systematic information concerning the effect of the peptide structure on the rate of drug release under physiological conditions. Herein we report the synthesis and the chemical reactivity of dipeptide esters of paracetamol, 4, encompassing a wide range of amino acid residues to evaluate the suitability of dipeptide esters as potential cyclization-activated prodrugs of paracetamol. In addition, the potential hepatotoxicity of several paracetamol derivatives was studied by evaluating the effect on the hepatic levels of glutathione in mice.Paracetamol esterification was based on the O-(benzotriazol-1-yl)-N,N,N 0 ,N 0 -tetramethyluronium 0960-894X/$ -see front matter Ó