Acid-hydrolases and nitrogen mustard cytotoxicity
Cohen, A.M.
Toxicology and Applied Pharmacology 43(1): 85-97
1978
ISSN/ISBN: 0041-008X PMID: 625766 Document Number: 136929
The role of acid hydrolases in the cytocidal antitumor action of nitrogen mustard (HN2) in rat intestine crypt epithelial cells was studied. An 8-fold increase in crypt cell .beta.-glucuronidase activity was observed 24 h after HN2 injection (2 mg/kg, i.p.). The activity of acid phosphatase and cathepsin D was not significantly altered by HN2 administration. Inhibition of DNA synthesis and widespread pycnosis and karyorrhexis of crypt cells preceded significant increased in .beta.-glucuronidase activity. Loss of intestinal DNA prelabeled with 3H-5-iodo-2'-deoxyuridine occurred subsequent to significant increases in .beta.-glucuronidase activity. A single injection of cycloheximide (1 mg/kg, i.p.) given 30 min before or 30 min after HN2 delayed the development of crypt cell histopathology. A 2nd injection of cycloheximide 8 h after HN2 prevented further development of crypt histopathology and completely blocked the increase in .beta.-glucuronidase activity and the loss of prelabeled DNA observed 24-30 h after HN2 alone. Acid hydrolases do not play a major role in initiation of the processes responsible for the death of proliferating crypt cells exposed to HN2. 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.