The kidney is the predominant organ involved in regulation of extracellular volume and in control of electrolyte and acid base balance. The kidney is often the main site for excretion of many drugs and drug metabolites and is therefore exposed to a variety of potential toxicants. The renal medulla offers unique problems concerning nephrotoxicity. Because of the low blood flow to the medulla, relatively less potential toxicant might enter this region via the bloodstream than in the cortex. The formation of urine begins at the glomerulus where an ultrafiltrate of plasma is formed. In addition, active secretion of toxicants occurs in the proximal tubule which can result in high intracellular concentrations of a chemical. The proximal tubule is therefore uniquely susceptible to aminoglycoside toxicity due to filtration and the presence of anionic binding sites along the luminal membrane. Any or all of these functions could become targets for toxicants.

The interaction of a bioengineered serpin (LEX032) with human leukocyte proteinase 3 (PR 3) has been investigated. LEX032 was found to be a time-dependent inhibitor of PR 3, forming a highly-stable enzyme-inhibitor complex (Ki 12 nM).

This chapter discusses that optical activity is caused by molecular asymmetry and that nonsuperimposable mirror-image structures results from this molecular asymmetry. There is a hypothesis that the chiral nature of compounds is because of the fact that carbon constituents can have a non-planar spatial arrangement giving rise to nonsuperimposable mirror images. Most naturally occurring medicinal agents exist in their optically active or single isomer form, such as quinidine and quinine, (-)-morphine, and (+)-digitoxin. However, many synthetic chemicals are produced as the optically inactive racemate. Because of potential pharmacological, pharmacokinetic, and toxicological issues, some scientists suggest that only single isomers should be considered for drug development and regulatory approval. Pharmacokinetic investigations into the disposition of enantiomers have enhanced the understanding of racemic drug action and have helped to understand previously inexplicable pharmacodynamic outcomes following administration of racemates to patients.

A clear consensus developed that toxicology will be driven by advances in related fields. New technology and knowledge developed by all relevant disciplines, therefore, must be integrated into toxicology; progress in toxicology demands that the discipline must increasingly address good science and the scientific method. Issues of critical importance to the field, such as risk estimation of the health effects of chemical and physical agents and the education of toxicologists, can only be addressed by meeting these objectives.

Large doses of the cephalosporin antibiotic, cephaloridine, produce acute proximal tubular necrosis in humans and in laboratory animals. Cephaloridine is actively transported into the proximal tubular cell by an organic anion transport system while transport across the lumenal membrane into tubular fluid appears restricted. High intracellular concentrations of cephaloridine are attained in the proximal tubular cell which are critical to the development of nephrotoxicity. There is substantial evidence indicating that oxidative stress plays a major role in cephaloridine nephrotoxicity. Cephaloridine depletes reduced glutathione, increases oxidized glutathione and induces lipid peroxidation in renal cortical tissue. The molecular mechanisms mediating cephaloridine-induced oxidative stress are not well understood. Inhibition in gluconeogenesis is a relatively early biochemical effect of cephaloridine and is independent of lipid peroxidation. Furthermore, cephaloridine inhibits gluconeogenesis in both target (kidney) and non-target (liver) organs of cephaloridine toxicity. Since glucose is not a major fuel of proximal tubular cells, it is unlikely that cephaloridine-induced tubular necrosis is mediated by the effects of this drug on glucose synthesis.

Chronic progressive nephropathy is a spontaneous disease common among aging laboratory rats, often making it difficult to distinguish age-related from drug-related effects in chronic toxicity studies. Morphological changes of the kidney that occur with age include thickening of glomerular and proximal tubular basement membranes, mesangial proliferation, fusion of foot processes, and, ultimately, glomerular sclerosis. Proteinuria (specifically, albuminuria) is the most striking characteristic change in renal function of aging rats and, generally, correlates well with the severity of age-related glomerular pathology. Changes in tubular functions also may occur with aging but have not been investigated sufficiently. The pathogenesis of chronic progressive nephropathy is not known; however, hemodynamic adaptations after ad libitum consumption of protein-rich diets may be a contributing factor. High-protein diets increase glomerular pressures and flows, perhaps facilitating excretion of metabolic end products. These hemodynamic adaptations may impair the permselective properties of the glomerulus, leading to: enhanced accumulation of macromolecules in the mesangium, progressive mesangial expansion, and, ultimately, glomerular sclerosis. Indeed, decreasing total food or protein intake retards or prevents the progression of age-related nephropathy. Inasmuch as chronic toxicity studies are complicated by a high incidence of spontaneous nephropathy, implementation of a restricted dietary regimen may improve detection of drug-induced toxicity.

HE UNUSUAL susceptibility of the mammalian kidney to the adverse effects of noxious chemicals can be attributed in large measure to the anatomic and physiologic features that are unique to the kidneys. The disproportionately large blood flow to the kidneys, which sustains its high rate of metabolism, results in greater delivery of bloodborne chemicals. During the process of salt and water reabsorption in the nephron, the tubular urine becomes enriched in those compounds that remain in the lumen, thus exposing the cells of the nephron to high concentrations of potential toxicants. Additionally, chemicals may accumulate within the cells of the proximal tubule if they are substrates for one of the organic ion transport systems that exist in this nephron segment. A more complete description of these features may be found in several recent reviews. 1.2 In contrast to a pharmacologic effect requiring interaction with a distinct receptor, the toxicity of many chemicals may often be the result of interruption of one or more essential cellular functions. This may occur following interaction of the chemical or its metabolite with critical macromolecules: proteins, nucleic acids, or lipids. Inasmuch as few chemicals in their native form react so intensely with such molecules, it is proposed that they undergo activation in proximity to the ultimate sites of action. The mechanisms that mediate this metabolic activation have been under close scrutiny, and several enzyme systems have been implicated. These include the drug-metabolizing enzymes often thought to be responsible for detoxification; that is, a chemical with relatively low toxicity may be metabolically altered by these same enzymes to form a compound that is more toxic. The biotransformation of xenobiotics to nephrotoxicants may occur in extrarenal organs, particularly the liver. Recently, more work has been directed toward the contribution of renal metabo

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.

Extracted propolis has been used for a long time as a remedy. However, if the release rate of propolis is not controlled, the efficacy is reduced. To overcome this issue, extracted propolis was added to a cryogel system. Propolis collected from southern Brazil was extracted using different methods and loaded at different concentrations into polyvinyl alcohol (PVA) and polyacrylic acid hydrogels as carrier systems. The material properties were investigated with a focus on the propolis release profiles and the cryogel antibacterial properties against 4 different bacteria, namely: Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, and Pseudomonas putida. Swelling studies indicated that the swelling of the hydrogel was inversely related to propolis content. In addition, propolis release studies indicated a decreased release rate with increased propolis loading. PVA and PVA/polyacrylic acid–loaded propolis were effective against all 4 bacteria studied. These results indicate that the efficacy of propolis can be enhanced by incorporation into hydrogel carrier systems and that hydrogels with higher concentrations of propolis can be considered for use as bactericide dressing.

Effects of age and sex on hexachloro-1,3-butadiene (HCBD) nephrotoxicity were determined 24 hours after a single dose (0, 25, 50, 100 or 200 mg/kg) in 28- and 63-day-old Fischer 344 rats. HCBD treatment significantly increased the kidney to body weight ratio but had little effect on the liver to body weight ratio. The 28-day-old rats were more susceptible to HCBD nephrotoxicity judged by elevated blood urea nitrogen, decreased renal cortical accumulation of p-aminohippurate and tetraethylammonium. Adult female rats (63-day-old) appeared to be more susceptible to HCBD nephrotoxicity than males at the low dose (50 mg/kg).

Cephaloridine produces necrosis of renal proximal tubular cells in humans and experimental animals. The mechanism responsible for this nephrotoxicity still remains unclear. In the present study, cephaloridine toxicity and concomitant changes in tissue glutathione content were determined in rabbits, rats, and mice. Kidney toxicity was evaluated as alterations in kidney-to-body weight ratio, blood urea nitrogen, and kidney slice accumulation of p-aminohippurate and tetraethylammonium. The results demonstrate that cephaloridine is most nephrotoxic to rabbits, intermediate in toxicity to rats, and least toxic to mice, confirming previous histopathological findings. Furthermore, cephaloridine produced a dose-related depletion of glutathione in the renal cortex but not in the medulla shortly after the injection. The relative susceptibility of these three species to glutathione depletion paralleled species differences in nephrotoxicity of cephaloridine. In addition, pretreatment of animals with diethyl maleate potentiated cephaloridine nephrotoxicity, strongly suggesting a relationship between glutathione depletion and cephaloridine toxicity.