Induction and exacerbation of hyaline droplet formation in the proximal tubular cells of the kidneys from male rats receiving a variety of pharmacological agents

Read, Nicholas G.; Astbury, Paul; Morgan, R.J.I.; Parsons, D.N.; Port, Christopher John

doi:10.1016/0300-483x(88)90198-9

Cited by 23 publications

(7 citation statements)

References 19 publications

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“…In fact, taking into account the basic and lipophilic properties of the molecule of LTG together with the carrier specificity of this protein for lipophilic ligands, it can be suggested that LTG, when bounded to the α ‐2U‐globulin, makes it more resistant to hydrolysis and/or, when accumulated in the lysosomes, has a direct inhibitory effect on lysosomal function. This reduction of the proteolytic breakdown of α ‐2U‐globulin occurs in the proximal tubule lysosomes, which are located in the cortical region of the kidney [6,7].…”

Section: Discussionmentioning

confidence: 99%

“…In the male rat, besides a good distribution of the antiepileptic drug through all organs and tissues, an accumulation of LTG in the kidneys was observed [5]. This accumulation was attributed to alterations in the renal handling of α ‐2U‐globulin in this species and gender [6,7]. It was suggested that this effect could partly explain the maintenance of LTG serum concentrations over a long period of time [8].…”

Section: Introductionmentioning

confidence: 99%

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Lamotrigine kidney distribution in male rats following a single intraperitoneal dose

Castel‐Branco

Falcão

Figueiredo

et al. 2004

Fundamemntal Clinical Pharma

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As it has been previously shown that lamotrigine (LTG) accumulates in the kidney of male rats, the purpose of the present investigation was to characterize the kidney profiles of LTG and its kidney distribution pattern in male rats, in order to confirm if a preferential distribution exists and to analyse if it does or does not affect the LTG systemic pharmacokinetics. Adult male Wistar rats were intraperitoneally injected with 5, 10 and 20 mg/kg of LTG. The concentration-time profiles of LTG in plasma and whole kidney were determined over 120 h postdose. The distribution of LTG in the rat kidney was investigated in another group of rats by measuring LTG levels in the renal cortex and medulla. The LTG plasma concentration-time profiles revealed a linear relationship with dose. However, a slight increase in the LTG elimination half-life with dose was observed. In contrast, a nonlinear relationship was established between LTG kidney levels and the dose administered. Consequently, nonparallel patterns were observed between LTG plasma and kidney profiles. The LTG kidney distribution pattern revealed an accumulation of LTG in the renal cortex. The present study demonstrated that LTG distributes preferentially to the kidneys of the male rat in a dose-dependent manner and suggests that such distribution may slightly affect the systemic kinetics of the drug.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lamotrigine kidney distribution in male rats following a single intraperitoneal dose

Castel‐Branco

Falcão

Figueiredo

et al. 2004

Fundamemntal Clinical Pharma

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show abstract

“…273 Ultrastructural examination reveals membrane-bound bodies often containing crystalloid structures composed of arrays of an ordered electron-dense lattice with distinct periodicity, features suggestive of crystalline protein (Figure 10.6b). 277 Drugs that enhance the accumulation of hyaline droplets in the rat may also accelerate the development of the specific rat glomerulosclerosis and the development of renal tubular neoplasms. Hyaline droplets that form after administration of xenobiotics may attain much larger sizes and contain more prominent angular crystalloid structures.…”

Section: Hyaline Dropletsmentioning

confidence: 99%

Urinary Tract

Greaves

2012

Histopathology of Preclinical Toxicity Studies

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“…Levamisole, a drug used as an anthelmintic, in cancer chemotherapy, and in the treatment of rheumatoid arthritis in humans, falls into the CIGA category because it induces both hyaline droplet and c2u-g accumulation in male rats (136). Based on an absence of elevated levels of urinary NAG in patients receiving 150mg levamisole per day for 26 weeks, there is little evidence to indicate that this compound is nephrotoxic in humans (166).…”

Section: Pathologic Features Of A-globulin Nephropathymentioning

confidence: 99%

Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

Hard

Rodgers

Baetcke

et al. 1993

Environ Health Perspect

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This review paper examines the relationship between chemicals inducing ewessive accumulation of a2u-globulin (ai21g) (CIGA) in hyline droplets inmale rat kidneys and the subsequent development of nephoit and rnal tubule nopaia in the male rt. This dose-responsive hyaline droplet accumulation distinguishes CIGA carcinogens fromclssical renal carcinogens. CIGA carcinogens also do not appear to react with DNA and are generally negative in short-term tests for genotoxicity. CIGA or their metabolites bind specifically, but reversibly, tomale rat a2,-g The resulting complex appears to be more resistant to hydrolytic degradation in the proximaltubule than native, unbound a2,-g Singlecell necrosis of the tubule epithelium, with associated granular cast formation and papillary mineralization, is followed by sustained regenerative tubule cell prolifertin, foci oftubulehyerl a inthe aovoited pronal bules, and renal tubule tumor Although stnrcturally similar proteins have been detected in other species, including hu_ms, renal lesios characteristic Of a2,-g nephropathy have not been observed. Epidemiologic investigation has not specifically examined the CIGA hypothesis for humans. Based on cancer bioassays, hormone manipulation studies, investigations in an ae,-g-deficient strain of rat, and other laboratory data, an increased proliferative response caused by chemically induced cytotoxicity appears to play a role in the development ofrenal tubule tumors in male rats Thus, it is reasonable to suggest that the renal effects induced in male rats by chemicals causing a2.-g accumulation are unlikely to occur in humans. IntroductionFor most hazardous chemicals, adequate human data are not available, and risk analyses must rely on information from laboratory studies of rats or mice. The inference that the results ofanimal experiments can be applied to humans is a fundamental principle of all toxicologic research. This analysis deals with a specific case, however, where the male rat seems to respond in a manner different from other laboratory species. The possibility of a unique response in the rat among laboratory animals raises questions about the applicability of the rat data to other species, including humans. Our review evaluates the matter of human 'Medical Research Council relevance and describes the types of information needed for hazard assessment of such chemicals.A variety of organic chemicals have produced specific renal lesions in male rats in the form of a protein (hyaline) droplet nephropathy accompanied by accumulation of a2%-globulin (a2.-g) [reviewed in (1,2)]. Among the chemicals tested are paraffins (3,4), decalin (decahydronaphthalene) (5,6), petroleum-based and synthetic fuels (7), military aviation propellants (8), and 2,2,4-trimethylpentane (TMP) (9). As seen in Table 1, which lists a sampling ofchemicals that have been tested, many are of considerable regulatory and commercial interest. For example, isophorone is a chemical intermediate of major industrial importance. Aviation and automotive fuels fit i...

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Induction and exacerbation of hyaline droplet formation in the proximal tubular cells of the kidneys from male rats receiving a variety of pharmacological agents

Cited by 23 publications

References 19 publications

Lamotrigine kidney distribution in male rats following a single intraperitoneal dose

Lamotrigine kidney distribution in male rats following a single intraperitoneal dose

Urinary Tract

Hazard evaluation of chemicals that cause accumulation of alpha 2u-globulin, hyaline droplet nephropathy, and tubule neoplasia in the kidneys of male rats.

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