Identification of a Mechanism by Which the Methylmercury Antidotes<i>N</i>-Acetylcysteine and Dimercaptopropanesulfonate Enhance Urinary Metal Excretion: Transport by the Renal Organic Anion Transporter-1

Koh, Albert S.; Simmons-Willis, Tracey A.; Pritchard, John B.; Grassl, Steven M.; Ballatori, Nazzareno

doi:10.1124/mol.62.4.921

Cited by 70 publications

(56 citation statements)

References 27 publications

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“…NAC acts as a cysteine pro-drug and a GSH precursor [17]. It can reduce disulfide bonds in proteins [14,18], scavenge free radicals [15] and bind metals to form complexes [19]. This can explain our results, where the unusual protective effect of NAC on lenticular epithelium, was observed.…”

Section: Resultssupporting

confidence: 54%

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Antioxidants Prevention of Diabetic Damage in the Organ Culture Bovine Lenses

Dovrat¹

2012

Metabolomics

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Oxidative stress represents a mechanism which could lead to diabetic cataract. We exposed bovine lenses in culture conditions for two weeks to high glucose concentration (450 mg%) and investigated the damage to the lens and possible protection by special antioxidants -N-acetyl-L-cysteine (NAC) and the zinc complex of desferrioxamine (DFO), a selective chelator for iron. We monitored the optical quality of the lenses and the oxidation of the epithelium with dichlorofluorescein (DCF) assay, as well as the changes in lens proteins profile by 2D gel electrophoresis. Under high glucose changes in lens focal length, increased oxidation, and changes in lens crystalline were observed. NAC and Zn-DFO nearly completely protected the lenses; DFO showed only partial protection. The results demonstrated that antioxidants should be considered as treatment modality protecting the lens from high glucose damage. It is proposed that a combination of NAC and Zn/DFO could prove highly efficient.the presence of high glucose concentrations (450 mg %), mimicking the diabetic state, and examined the protection bestowed by the DFO complexes and NAC, on the injurious processes on the lenses. We used a unique system of intact bovine lenses, maintained for a longterm, under culture conditions. This system allows for direct exposure to a pre-set glucose concentration, and monitoring the effects on lens transparency with a highly sensitive optical method [20]. The system can detect early optical damage to lenses, which cannot be detected by other methods often used. At the completion of the culture period lens epithelium and lens proteins were analyzed.It was anticipated that the extent of protection exerted on the lens, in this system, will be indicative of the involvement of iron as a catalyst and of free radicals as causative agents, in the damage to the diabetic lens. Materials and Methods Lens organ culture systemLenses were excised in a delicate operation from eyes obtained from 1-year-old male calves under sterile conditions, 2-4 hours after enucleating. From each animal one eye is used for experimental treatment and the other eye serves as control. Each lens is placed in a specially designed culture container, which we have developed [21]. The culture medium consists of M199 with Earl's balanced salt solution, supplemented with 5.96g/L HEPES, 3% dialyzed fetal calf serum and antibiotics (penicillin 100 U/ml and streptomycin 0.1 mg/ ml). Our intact lens culture system mimics the lens conditions inside the eye and makes it possible to keep lenses for long-term studies for

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Section: Resultssupporting

confidence: 54%

“…This involved the employment of N-acetyl cysteine (NAC), to scavenge free radicals [14][15][16] and to replenish reduced sulfhydryl residues [14][15][16][17][18][19]. NAC is a precursor of glutathione -the major source of cellular sulfhydryl groups and acts as a potent an anti-inflammatory agent.…”

Section: Introductionmentioning

confidence: 99%

Antioxidants Prevention of Diabetic Damage in the Organ Culture Bovine Lenses

Dovrat¹

2012

Metabolomics

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“…Indeed, the burden of characterizing each novel drug entity is great, and without more powerful in silico methods to facilitate predictions, the advancement of the field will be limited by our capacity to perform in vitro experiments. [151], [150], [143], [195], [176], [41], [42] Propionate …”

Section: Resultsmentioning

confidence: 99%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

201

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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“…As mentioned above, in the kidneys, this transporter is localized exclusively in the basolateral membrane of proximal tubular epithelial cells (Kojima et al, 2002;Motohashi et al, 2002). There is some evidence from studies in Xenopus laevis oocytes implicating this transporter in the cellular uptake of NAC and DMPS Sconjugates of CH 3 Hg + (CH 3 Hg-S-NAC and (CH 3 Hg-S) 2 -DMPS, respectively; Koh et al, 2002). Thus, CH 3 Hg-S-Cys may also be taken up at the basolateral membrane of proximal tubular epithelial cells by OAT1.…”

Section: Molecular Mimicry and The Renal Transport Of Ch 3 Hg +mentioning

confidence: 99%

“…However, Koh et al (2002) proposed that the efflux of CH 3 Hg + across the luminal plasma membrane is mediated by MRP2. MRP2 is an ATP-binding cassette (ABC) transport protein that is localized in the luminal membrane of the proximal tubule (Schaub et al, 1997(Schaub et al, , 1999 and has been shown to be involved in the transport of glutathione-S conjugates of other metals (Leslie et al, 2004).…”

Section: Molecular Mimicry and The Renal Transport Of Ch 3 Hg +mentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

649

460

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Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

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Identification of a Mechanism by Which the Methylmercury AntidotesN-Acetylcysteine and Dimercaptopropanesulfonate Enhance Urinary Metal Excretion: Transport by the Renal Organic Anion Transporter-1

Cited by 70 publications

References 27 publications

Antioxidants Prevention of Diabetic Damage in the Organ Culture Bovine Lenses

Antioxidants Prevention of Diabetic Damage in the Organ Culture Bovine Lenses

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Molecular and ionic mimicry and the transport of toxic metals

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