Promutagenic alkyl lesions are induced in the tissue DNA of animals treated with isoniazid.
Further studies have been carried out to determine mechanisms for the toxic and carcinogenic properties of isoniazid (INH) in laboratory animals. 1. Single doses of INH (1.1 mg per mouse), which if given continuously to Swiss mice result in a 50% incidence of lung tumours, lead to the formation of approximately 0.5 and approximately 0.3 mumol O6-methylguanine per mol/guanine in the DNA of liver and lung, respectively. 2. Repeated doses of INH result in a progressive decrease in the levels of O6-methylguanine in lung DNA and relatively constant levels in hepatic DNA. Treatment with equimolar doses of hydrazine result in higher levels of alkylation in the DNA of liver than of lung. 3. Comparable experiments in Wistar rats show that treatment with hydrazine is very much more effective than INH in inducing the alkylation of liver and lung DNA. 4. Immunocytochemical staining of cryostat sections of liver has been used to show that the formation of O6-methylguanine occurs mainly in the nuclei of hepatocytes. 5. These results demonstrate that treatment with INH leads to the alkylation of tissue DNA and suggest that this may arise via a hydrazine intermediate. The implications of the formation of highly promutagenic lesions in tissue DNA for INH induced toxicity and carcinogenicity are discussed.
Saffhill
R
R
Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK.
Fida
S
S
Bromley
M
M
O'Connor
P J
PJ
D000478:Alkylation; D000818:Animals; D004247:DNA / Q000032:analysis*; D004249:DNA Damage; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity*; D008099:Liver / Q000032:analysis / Q000378:metabolism*; D008168:Lung / Q000032:analysis / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains; D013194:Staining and Labeling
D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D007538:Isoniazid