Lack of biliary excretion of Cd linked to an inherent defect of the canalicular isoform of multidrug resistance protein (cMrp) does not abnormally stimulate accumulation of Cd in the Eisai hyperbilirubinemic (EHB) rat liver

Sakata, Naoki; Lai, Yurong; Arizono, Koji; Kitajima, Takuya; Inoue, Hitoshi

doi:10.1007/s002040050395

Cited by 9 publications

(3 citation statements)

References 13 publications

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“…MDR and MRP transport proteins are generally multispecific, transporting a variety of structurally unrelated molecules, including organometallic complexes. Evidence has been presented that MRP2 mediates biliary transport of metals complexed with GSH, including arsenic and cisplatin, and possibly copper, cadmium, and mercury, whereas cells overexpressing MDR1 are more resistant to cationic lipophilic metal complexes, indicating transport of the metal complexes on MDR1 (2,(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84). Whether other multispecific transporters also mediate transport of organometallic complexes has not yet been examined.…”

Section: Nazzareno Ballatorimentioning

confidence: 99%

Transport of toxic metals by molecular mimicry.

Ballatori

2002

Environ Health Perspect

239

151

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Intracellular concentrations of essential metals are normally maintained within a narrow range, whereas the nonessential metals generally lack homeostatic controls. Some of the factors that contribute to metal homeostasis have recently been identified at the molecular level and include proteins that mediate import of essential metals from the extracellular environment, those that regulate delivery to specific intracellular proteins or compartments, and those that mediate metal export from the cell. Some of these proteins appear highly selective for a given essential metal; however, others are less specific and interact with multiple metals, including toxic metals. For example, DCT1 (divalent cation transporter-1; also known as NRAMP2 or DMT1) is considered to be a major cellular uptake mechanism for Fe(2+) and other essential divalent metals, but this protein also mediates uptake of Cd(2+), Pb(2+), and possibly of other toxic divalent metals. The ability of nonessential metals to interact with binding sites for essential metals is critical for their ability to gain access to specific cellular compartments and for their ability to disrupt normal biochemical or physiological functions. Another major mechanism by which metals traverse cell membranes and produce cell injury is by forming complexes whose overall structures mimic those of endogenous molecules. For example, it has long been known that arsenate and vanadate can compete with phosphate for transport and metabolism, thereby disrupting normal cellular functions. Similarly, cromate and molybdate can mimic sulfate in biological systems. Studies in our laboratory have focused on the transport and toxicity of methylmercury (MeHg) and inorganic mercury. Mercury has a high affinity for reduced sulfhydryl groups, including those of cysteine and glutathione (GSH). MeHg-l-cysteine is structurally similar to the amino acid methionine, and this complex is a substrate for transport systems that carry methionine across cell membranes. Once MeHg has entered the cell, some of it binds to GSH, and the resulting MeHg-glutathione complex appears to be a substrate for proteins that mediate cellular export of glutathione S-conjugates, including the apically located MRP2 (multidrug resistance-associated protein 2) transporter, a member of the adenosine triphosphate-binding cassette protein superfamily. Because other toxic metals also form complexes with endogenous molecules, comparable mechanisms may be involved in their membrane transport and disposition.

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Section: Nazzareno Ballatorimentioning

confidence: 99%

Transport of toxic metals by molecular mimicry.

Ballatori

2002

Environ Health Perspect

239

151

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“…Second, coworkers (1996, 1997) demonstrated enhanced transport of a glutathione-platinum complex in membrane vesicles prepared from a tumor cell line overexpressing MRP. Third, mutant rats that lack mrp2 activity (TR -, GY, or EHBR rats), exhibit impaired ability to transport several metals into bile, including zinc, excess copper, silver, cadmium, and methylmercury Dijkstra et al 1996Dijkstra et al , 1997Houwen et al 1990;Sugawara et al 1997). In contrast, basal excretion of endogenous copper is unaffected in these mutant rats (Houwen et al 1990).…”

Section: Mrp/abcc-mediated Excretion Of Gsh Complexes and Other Organmentioning

confidence: 99%

Transport of nonessential metals across mammalian cell membranes

Ballatori

Madejczyk

2005

Topics in Current Genetics

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Nonessential metals are opportunistic. They compete with essential metals for binding to various cofactors, receptors, transcription factors, transporters, and other metalloproteins, and in doing so they gain access to various cellular and subcellular compartments, and interfere in the functions of the essential metals. Because of their high chemical reactivities, nonessential metals also interact nonspecifically with a multitude of other cellular ligands, and interfere with many other cellular processes. In general, nonessential metals cross biological membranes by three mechanisms. First, as indicated above, they often compete with endogenous metals for transport on the various metal ion transporters, pumps, and channels. Alternatively, they may form complexes that are then substrates for other ion and organic solute transporters and pumps. A third general mode of transport involves both signal-induced (e.g. receptor-mediated) and constitutive endocytosis of metals ions and metal complexes. In contrast with these mediated transport pathways, simple diffusion appears to play only a minor role in metal transport. Collectively, these permeation pathways allow toxic metals to reach diverse cellular and subcellular targets, but can also be exploited in the design of therapeutic strategies aimed at accelerating the removal of these toxic elements from the body.

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“…The function of Mrp2/Abcc2 has been studied extensively by comparing the hepatobiliary transport across the bile canalicular membrane via normal and Mrp2-deficient mutant animals or chemical knockout models using Mrp2-specific inhibitors (Suzuki and Sugiyama, 1998;Keppler et al, 2000). The Mrp2-deficient animals, such as transport-deficient (TRϪ) and Eisai hyperbilirubinemic rats (EHBRs), have been used in the last decade as tools to study the importance of Mrp2/Abcc2-mediated hepatobiliary elimination (Sugawara et al, 1997). For instance, Yamazaki et al (1996) reported that the biliary secretion and total clearance of pravastatin were higher in normal rats, which resulted in 2-fold reduction in steady-state plasma concentration compared with Mrp2-deficient EHBRs.…”

mentioning

confidence: 99%

Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

Hu¹,

Sampson²,

Heyde³

et al. 2009

Drug Metab Dispos

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Madin-Darby canine kidney cells, suggesting that it is a substrate, not an inhibitor, of the MRP2/ABCC2 transporter. To investigate the mechanism for the nonlinear pharmacokinetics, bile duct-cannulated rats were used to obtain time profiles of plasma concentration, biliary, and urinary excretion after intravenous administration at various doses. The plasma clearance increased remarkably with decreased dose, from 1.5 ml/min/kg at 5 mg/kg to 14.9 ml/min/kg at 0.05 mg/kg. A dose-dependent biliary excretion also was observed. The results revealed that saturation of hepatobiliary secretion played a role in the dose-dependent changes in total body clearance and biliary clearance. Saturating concentrations of the Mrp2/Abcc2 substrate, BPCPU, causing decreased hepatobiliary clearance could be the major cause for the nonlinear pharmacokinetics observed in rats.

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Lack of biliary excretion of Cd linked to an inherent defect of the canalicular isoform of multidrug resistance protein (cMrp) does not abnormally stimulate accumulation of Cd in the Eisai hyperbilirubinemic (EHB) rat liver

Cited by 9 publications

References 13 publications

Transport of toxic metals by molecular mimicry.

Transport of toxic metals by molecular mimicry.

Transport of nonessential metals across mammalian cell membranes

Saturation of Multidrug-Resistant Protein 2 (Mrp2/Abcc2)-Mediated Hepatobiliary Secretion: Nonlinear Pharmacokinetics of a Heterocyclic Compound in Rats after Intravenous Bolus Administration

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