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Time Course and Dose-Response Characteristics of Aflatoxin B₁ Effects on Rat Liver RNA Polymerase and Ultrastructure¹

Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

Treatment of 100-g male Fischer rats with an i.p. dose of 1 mg/kg of aflatoxin B₁ causes a rapid and marked inhibition of the activity of liver DNA-dependent RNA polymerase. Over a period of 36 hr after dosing, ultrastructural alterations of the liver cell nucleolus generally correlate with the inhibition of enzyme activity. Mg⁺⁺-activated and Mn⁺⁺-(NH₄)₂SO₄-activated RNA polymerase activities, 15 min after dosing, are maximally inhibited by about 60%; this inhibition continues to 12 hr. By 36 hr, enzyme activities have returned to pretreatment levels. Hepatocyte nucleoli 15 min after treatment show decreased prominence of nucleolonema, and nucleolar microsegregation is observed. Macrosegregation of granular and fibrillar nucleolar components (nucleolar capping) is demonstrated within 1 hr after treatment, and the segregation persists up to 12 hr. By 36 hr, reintegration of nucleolar components is observed.

Inhibition of RNA polymerase activity is directly related to aflatoxin B₁ dose, with a correlation coefficient of -0.89 for the Mg⁺⁺-activated system and -0.97 for the Mn⁺⁺-(NH₄)₂SO₄-activated system. Nucleolar disorganization is observable at 0.2 mg/kg aflatoxin B₁ but is not demonstrable at 0.1 mg/kg, a dose which is capable of a 5% inhibition of both types of enzyme activity. A decrease in nuclear RNA/DNA ratio is observed under conditions where RNA polymerase activity is decreased.

¹ Supported by Contract PH 43-62-468 from the National Cancer Institute.

² This report is based upon portions of a thesis submitted by R. S. P. in partial fulfillment of requirements for the Ph.D. degree.

Received 2/ 6/69. Accepted 7/16/69.