Acid hydrolases and nitrogen mustard cytotoxicity

Abstract

Acid Hydrolases and Nitrogen Mustard Cytotoxicity. Cohen, A. M. (1978). Toxicol. Appl. Pharmacol. 43 , 85–97. The role of acid hydrolases in the cytocidal action of nitrogen mustard (HN 2 ) in rat intestine crypt epithelial cells was studied. An eight-fold increase in crypt cel β-glucuronidase activity was observed at 24 hr after HN 2 injection (2 mg/kg, ip). The activity of acid phosphatase and cathepsin D was not significantly altered by HN 2 administration. Inhibition of DNA synthesis and widespread pycnosis and karyorrhexis of crypt cells preceded significant increases in β-glucuronidase activity. However, loss of intestinal DNA prelabeled with tritiated 5-iodo-2′-deoxyuridine occurred subsequent to significant increases in β-glucuronidase activity. A single injection of cycloheximide (1 mg/kg, ip) given at either 30 min before or 30 min after HN 2 delayed the development of crypt cell histopathology. A second injection of cycloheximde at 8 hr after HN 2 prevented further development of crypt histopathology and completely blocked the increase in β-glucuronidase activity and the loss of prelabeled DNA observed at 24–30 hr after HN 2 alone. These studies suggest that acid hydrolases do not play a major role in the initiation of the processes responsible for the death of proliferating crypt cells exposed to HN 2 . However, the results are consistent with a possible role for certain of these enzymes in the degradation and removal of dead cells from the crypt epithelium.