Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity

Lash, Lawrence H.

doi:10.1002/9780470439265.ch26

Cited by 4 publications

(6 citation statements)

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“…Fourth, bioactivation enzymes exist within renal epithelial cells, particularly those of the proximal tubules, that can metabolize many drugs and other chemicals to reactive and toxic forms. 44,47,48 The potential fates of drugs to which the kidneys are exposed are summarized in Fig. 1 .…”

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confidence: 99%

Renal Membrane Transport of Glutathione in Toxicology and Disease

Lash

2010

Vet Pathol

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Membrane transport processes, at both the plasma membranes and intracellular membranes, play critical roles in renal function and are a determining factor in the susceptibility of renal epithelial cells to blood-borne drugs and toxic chemicals. Proximal tubular epithelial cells possess a large array of transport proteins for organic anions, organic cations, and peptides on both basolateral and brush-border plasma membranes. Although these transporters function in excretion of waste products and reabsorption of nutrients, they also play a role in the susceptibility of the kidneys to drugs and other toxicants in the blood. The proximal tubules are typically the primary target cells because they are the first epithelial cell population exposed to such chemicals in either the renal plasma or glomerular filtrate and because of their large array of membrane transporters. Besides transport across the basolateral and brush-border plasma membranes, transport across intracellular membranes such as the mitochondrial inner membrane is a critical determinant of metabolite distribution. To illustrate the function of these transporters, carrier-mediated processes for transport of the tripeptide and antioxidant glutathione across the basolateral, brushborder, and mitochondrial inner membranes of the renal proximal tubule are reviewed. Studies are summarized that have identified the involvement of specific carrier proteins and characterized the role of these transporters in glutathione metabolism and turnover, susceptibility of the proximal tubules to oxidative and other stresses, and modulation in disease and other pathological processes.Keywords apoptosis, diabetic nephropathy, glutathione, mitochondria, organic anion transporters, oxidative stress, renal proximal tubule Membrane transport processes play critical roles in numerous physiological and pharmacological processes, including maintenance of cellular ion gradients, regulation of metabolite distribution, drug accumulation in target organs, and drug excretion. Membrane transport processes are central to the functions of the kidneys, and in particular of the proximal tubular epithelial cells, in ion and metabolite homeostasis, nutrient reabsorption, excretion of waste products, and drug distribution and metabolism. When considering exposure of the kidneys to drugs and potentially toxic chemicals, however, these basic physiological functions take on a new dimension because they are major contributory factors to the sensitivity of the kidneys to numerous blood-borne toxic chemicals.There are 4 key reasons the kidneys are frequent and sensitive targets for blood-borne drugs and toxic chemicals. First, the kidneys receive an inordinately high rate of blood flow in relationship to their weight (ie, 25% of cardiac output compared with 1-2% of body weight). Second, the process of glomerular filtration delivers all substances below a cut-off molecular weight in the plasma to the tubular lumen. Hence, whereas proteins below a molecular weight of 20 kDa freely pass through ...

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confidence: 99%

Renal Membrane Transport of Glutathione in Toxicology and Disease

Lash

2010

Vet Pathol

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“…Whereas the focus of most drug metabolism studies has been the liver, it became apparent that the kidneys have a significant capacity to carry out extensive oxidation, reduction, hydrolysis, and conjugation reactions. 33,34 Enzyme systems similar to those present in the liver and other extrarenal tissues are involved in renal drug metabolism. An important difference between the kidneys and other tissues is that many of the drug metabolism enzyme systems, such as CYPs, glutathione S-transferases (GSTs), and others, are differentially distributed among the different nephron cell populations.…”

Section: Drug Metabolismmentioning

confidence: 99%

“…A clinically important example of this is for acetaminophen. 34 Whereas the acute nephrotoxicity of acetaminophen is characterized by proximal tubular necrosis and is associated with metabolism by CYP, chronic nephrotoxicity of acetaminophen is characterized by papillary necrosis and interstitial fibrosis and is dependent on oxidation by prostaglandin synthetase in the inner medulla. This difference is largely due to the accumulation of acetaminophen in the cortex under acute exposure conditions and in the inner medulla under chronic exposure conditions.…”

Section: Drug Metabolismmentioning

confidence: 99%

“…Examination of renal activities of CYPs provides a clear illustration of this. For example, whereas rodent kidneys, particularly in the proximal tubular segments of the nephron, contain a large array of CYP enzymes that is very similar to that found in the liver, 33,34,39,40 human kidney expresses a much smaller number of CYP enzymes. [41][42][43] Additionally, the pattern of inducibility of both CYPs and Phase II enzymes such as GSTs or UDP-glucuronosyltransferases in the kidney differs between rodents and humans.…”

Section: Drug Metabolismmentioning

confidence: 99%

“…[41][42][43] Additionally, the pattern of inducibility of both CYPs and Phase II enzymes such as GSTs or UDP-glucuronosyltransferases in the kidney differs between rodents and humans. 44,45 Enzyme induction is the process by which prior or concurrent exposure to certain chemicals causes the increased expression of specific enzymes. For example, whereas CYP1A1/2, that metabolizes polycyclic aromatic hydrocarbons is expressed at low constitutive levels in rodent kidney, CYP1A1 is highly inducible; in contrast, this CYP enzyme is both not detectable and poorly inducible in human kidney.…”

Section: Drug Metabolismmentioning

confidence: 99%

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