Early changes in rat liver and kidney cells induced by thioacetamide.

Thioacetamide (TA), a drug effective in the control of orange decay (5), was found to induce liver cirrhosis, tumors (9), and cancer of the bile ducts (11) if fed to rats over a period of several months. The most striking effects, first described by Rather (28), are the doubling of nuclear vol ume, increased nucleolar and cell volumes, and altered basophilia of the cytoplasm. These changes are well developed within a few days of treatment and are largely reversible. Biochemical studies of the early effects of the drug show a considerable increase in nuclear ribonucleic acid (RNA) and protein, while the deoxyribonucleic acid (DNA) per nucleus remains the same (19, 34). Photo metric measurements of Feulgen-stained nuclei indicate that the early increase in nuclear volume is not associated with corresponding increases in the DNA content (15). After prolonged TA treat ment, i.e., 3-?5 months, the DNA content per nu cleus increases in direct proportion to the in creased nuclear volume (4, 12). The recent work of Nygaard et al. (20), using S35-labeled TA indicates that TA is rapidly me tabolized in the rat. More than 80 per cent of the radioactivity is excreted in the urine during the first 24 hours. This explains the need for continu ous treatment (addition of TA to the diet or daily injections) to maintain the effect induced by the drug. The liver, reported to be the only organ showing morphological changes after TA treat ment, does not concentrate S35-labeled TA. The bone marrow, thyroid, and adrenals do concen trate the labeled drug to a considerable degree temporarily, yet appear to remain unaffected. The early effect of the drug results in a disturb ance of the ribonucleoprotein system of the cell (19), whereas increased DNA synthesis and cell proliferation are responses to chronic intoxica-