Abstract
The pathogenesis of renal lesions induced by two types of papillotoxin was examined in male laboratory rats. The compounds used were halogenated alkylamines such as 2 bromoethanamine, or aromatic amines such as diphenylamine (DPA) and N-phenylanthranilie acid (N-PAA) - the latter of which was studied as a model of the fenamate nonsteroidal antiinflammatory drugs. Structure activity studies with haloalkylamines identified three new papillotoxins: 2-chloroethanamine, NN dimethyl 2-chloroethanamine and 3-bromopropanamine. The biological alkylating activities of these compounds (as measured by direct acting mutagenicity) correlated directly with papillotoxicity strongly implicating direct alkylation of papillary tissue in the mechanism of renal papillary necrosis (RPN). DPA and N-PAA induced RPN and proximal straight tubular necrosis after a single dose (lg/kg) or with more protracted administration (250 mg/kg for several weeks). A time course experiment with DPA demonstrated degeneration of the papillary vascular endothelium within three hours and RPN within nine hours. DPA also induced a marked Heinz body haemolytic anaemia, which developed independently of the renal lesions. Two hydroxylated derivatives of DPA were not papillotoxic, but did induce proximal tubular necrosis suggesting that an intermediate of oxidative metabolism is responsible for papillotoxicity. It is hypothesised that RPN results from co-oxygenative metabolism of aromatic amines in the vascular endothelium, during the synthesis of PGI2, and that benzoquinoneimine or semiquinone-type radicals are the proximate toxins. It is further hypothesised that proximal tubular necrosis may result from Cytochrome P-450 mediated epoxidation. The role of Tamm-Horsfall glycoprotein in relation to RPN and interstitial nephritis was examined in animals with ureteral obstruction. The present results, and a reexamination of the tissues from an earlier two year feeding experiment with DPA, strongly implicate RPN in the genesis of so called polycystic renal lesions.