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N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure.

Aremu DA, Madejczyk MS, Ballatori N - Environ. Health Perspect. (2008)

Bottom Line: In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats.Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals.In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.

ABSTRACT

Background: Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body.

Objectives: Using N-acetylcysteine (NAC), we aimed to devise a monitoring protocol for early detection of acute exposure or relatively low MeHg levels in a rodent model, and to test whether NAC reduces MeHg levels in the developing embryo.

Results: NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of various MeHg doses was excreted in urine 2 hr after injection of 1 mmol/kg NAC. In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus. In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats.

Conclusions: Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.

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Potential mechanism of NAC-stimulated renal excretion of MeHg. The MeHg–NAC complex spontaneously formed in the blood is a substrate for Oat1, an α-ketoglutarate–coupled anion exchanger at the basolateral membrane of proximal tubule cells. Once inside the cell, some of the MeHg will redistribute to other intracellular ligands, including the formation of the glutathione complex (MeHg–SG). The MeHg–NAC and MeHg–SG complexes are both substrates for Mrp2, an ATP-dependent transporter localized to the brush border membrane, which mediates efflux of these complexes from the renal tubular cells into the renal tubular lumen for excretion via the urine. Modified from Madejczyk et al. (2007).
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f6-ehp0116-000026: Potential mechanism of NAC-stimulated renal excretion of MeHg. The MeHg–NAC complex spontaneously formed in the blood is a substrate for Oat1, an α-ketoglutarate–coupled anion exchanger at the basolateral membrane of proximal tubule cells. Once inside the cell, some of the MeHg will redistribute to other intracellular ligands, including the formation of the glutathione complex (MeHg–SG). The MeHg–NAC and MeHg–SG complexes are both substrates for Mrp2, an ATP-dependent transporter localized to the brush border membrane, which mediates efflux of these complexes from the renal tubular cells into the renal tubular lumen for excretion via the urine. Modified from Madejczyk et al. (2007).

Mentions: Figure 6 illustrates a model that may explain the effects of NAC on urinary MeHg excretion. After oral NAC administration, NAC is rapidly absorbed from the gastrointestinal tract, and blood NAC levels rise quickly (Borgstrom et al. 1986; Rodenstein et al. 1978). NAC can spontaneously (i.e., nonenzymatically) form a thermodynamically stable mercaptide complex with MeHg to form MeHg–NAC. MeHg–NAC is an excellent substrate for Oat1 (Koh et al. 2002), a major renal basolateral membrane organic anion carrier, and thus MeHg–NAC can be transported from blood into the renal tubular cell via this carrier. It is important to note that NAC itself is also efficiently cleared by the kidney and excreted into urine in high concentrations (Borgstrom et al. 1986; Rodenstein et al. 1978). In humans the half-life of NAC in blood plasma is only 2 hr; this short half-life is due largely to NAC’s rapid urinary excretion (Borgstrom et al. 1986; Rodenstein et al. 1978). Approximately one-third of the NAC is excreted in urine during the first 12 hr after administration (Borgstrom et al. 1986); this half-life for NAC in blood is also consistent with the rapid acceleration of MeHg excretion observed during NAC administration, and with the rapid deceleration in MeHg excretion after NAC withdrawal (Figures 1–3).


N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure.

Aremu DA, Madejczyk MS, Ballatori N - Environ. Health Perspect. (2008)

Potential mechanism of NAC-stimulated renal excretion of MeHg. The MeHg–NAC complex spontaneously formed in the blood is a substrate for Oat1, an α-ketoglutarate–coupled anion exchanger at the basolateral membrane of proximal tubule cells. Once inside the cell, some of the MeHg will redistribute to other intracellular ligands, including the formation of the glutathione complex (MeHg–SG). The MeHg–NAC and MeHg–SG complexes are both substrates for Mrp2, an ATP-dependent transporter localized to the brush border membrane, which mediates efflux of these complexes from the renal tubular cells into the renal tubular lumen for excretion via the urine. Modified from Madejczyk et al. (2007).
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2199271&req=5

f6-ehp0116-000026: Potential mechanism of NAC-stimulated renal excretion of MeHg. The MeHg–NAC complex spontaneously formed in the blood is a substrate for Oat1, an α-ketoglutarate–coupled anion exchanger at the basolateral membrane of proximal tubule cells. Once inside the cell, some of the MeHg will redistribute to other intracellular ligands, including the formation of the glutathione complex (MeHg–SG). The MeHg–NAC and MeHg–SG complexes are both substrates for Mrp2, an ATP-dependent transporter localized to the brush border membrane, which mediates efflux of these complexes from the renal tubular cells into the renal tubular lumen for excretion via the urine. Modified from Madejczyk et al. (2007).
Mentions: Figure 6 illustrates a model that may explain the effects of NAC on urinary MeHg excretion. After oral NAC administration, NAC is rapidly absorbed from the gastrointestinal tract, and blood NAC levels rise quickly (Borgstrom et al. 1986; Rodenstein et al. 1978). NAC can spontaneously (i.e., nonenzymatically) form a thermodynamically stable mercaptide complex with MeHg to form MeHg–NAC. MeHg–NAC is an excellent substrate for Oat1 (Koh et al. 2002), a major renal basolateral membrane organic anion carrier, and thus MeHg–NAC can be transported from blood into the renal tubular cell via this carrier. It is important to note that NAC itself is also efficiently cleared by the kidney and excreted into urine in high concentrations (Borgstrom et al. 1986; Rodenstein et al. 1978). In humans the half-life of NAC in blood plasma is only 2 hr; this short half-life is due largely to NAC’s rapid urinary excretion (Borgstrom et al. 1986; Rodenstein et al. 1978). Approximately one-third of the NAC is excreted in urine during the first 12 hr after administration (Borgstrom et al. 1986); this half-life for NAC in blood is also consistent with the rapid acceleration of MeHg excretion observed during NAC administration, and with the rapid deceleration in MeHg excretion after NAC withdrawal (Figures 1–3).

Bottom Line: In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats.Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals.In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.

ABSTRACT

Background: Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body.

Objectives: Using N-acetylcysteine (NAC), we aimed to devise a monitoring protocol for early detection of acute exposure or relatively low MeHg levels in a rodent model, and to test whether NAC reduces MeHg levels in the developing embryo.

Results: NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of various MeHg doses was excreted in urine 2 hr after injection of 1 mmol/kg NAC. In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus. In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats.

Conclusions: Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.

Show MeSH
Related in: MedlinePlus