Relationships between structure and induction of hyaline droplet accumulation in the renal cortex of male rats by aliphatic and alicyclic hydrocarbons

Abstract

A rapidly growing list of hydrocarbons has been reported to induce morphological changes in the kidney of adult male rats, beginning with hyaline droplet accumulation (HDA) followed by the development of granular casts, later on chronic nephrosis as sequela, and finally renal adenomas and carcinomas. The present study focuses on identifying structure-based properties common to HDA-inducing aliphatics and cycloaliphatics. On the basis of rank-ordered activities reported in the literature, a calculated n-octanol-water partition coefficient above 3.5 and the presence of an isopentyl structural moiety appear to be associated with HDA-inducing activity in aliphatics. A binding site model for highly active aliphatics has been derived by superimposing their minimum energy conformations along the common isopentyl substructure and calculating the union volume of their respective van der Waal (VDW) volumes. Generalization of this model to include cycloaliphatics has been achieved by maximizing the steric overlap of the VDW volumes of the compounds with their binding site union volume. HDA-inducing cycloaliphatics are correctly identified on the basis of their negligible excess volume. This approach has been used to predict the HDA-inducing activity of previously untested compounds. Eighteen aliphatic/cycloaliphatic hydrocarbons were screened in a study on adult male Wistar rats treated with 250 mg/kg per day for 5 days. Azan-stained kidney sections were semiquantitatively evaluated for the presence of HDA. The predicted and observed HDA activities were in very good agreement.

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

“…Using an in vitro incubation system with renal cortex lysosomes prepared from male rats, Lehman-McKeeman et al (91) (109). Based on data for a number of light hydrocarbons, Bomhard et al (109) surmised that an n-octanol/water partition coefficient above 3.5 and the presence ofan isopentyl structural moiety are associated with increased hyaline droplet formation in male rats.…”

The structures of α2u-globulin and its complex with a hyaline droplet inducer

“…The hallmark of this acute toxicity is the accumulation of hyaline droplets within the epithelial cells of the renal proximal convoluted tubule. Compounds that induce this toxicity include d-limonene (DL, p-mentha-1,8-diene), decalin, 1,3,5-trinitrobenzene, 2,2,4-trimethylpentanol, gabapectin (an anti-epileptic/anticonvulsant therapeutic agent), 1,8-cineole and p-dichlorobenzene (Stonard et al, 1986;Bomhard et al, 1990;Ridder et al, 1990;Borghoff et al, 1991;Takahashi et al, 1993;Kristiansen & Madsen, 1995;Kim et al, 1997). Interestingly, a number of hyaline-droplet inducers have been tested on female rats, male and female mice, guinea pigs, dogs and monkeys, and have been shown not to induce any accumulation of hyaline droplets (Lehman-McKeeman & Caudill, 1992a,b).…”

Interpretation of male rat renal tubule tumors.

“…Structure-activity relationships for chemicals that induce ux2u-g accumulation in the male rat kidney are not well defined, although there appear to be dimensional requirements to fit the protein pocket, a requirement for a degree of lipophilicity, and a need for an electronegative atom in the molecule or its active metabolite (92 …”