Modulation of hepatic transcription and translation during early stages of aflatoxin B1 carcinogenesis

Abstract

Isolated rat hepatocytes have been used to study the transcription and translation processes at varied time intervals after administration of a single dose (6 mg/kg) of hepatocarcinogen aflatoxin B₁ (AFB₁). The effects of AFB₁ during the first 24 h of drug treatment show a characteristic inhibition followed by periods of rapid recovery and also a hyperactive state when both heterogeneous nuclear RNA (HnRNA) transcription and cytoplasmic translation processes reach about 200% of control. Analysis of [³H]orotic acid pulse-labeled HnRNA and cytoplasmic polyadenylic acid (poly (A)) containing mRNA on sucrose gradients under conditions which prevent aggregation show a stepwise reduction in the total isotopic incorporation as well as in the size distribution during the first 9 h of AFB₁ treatment. Between 9 and 24 h after AFB₁ treatment, there is a recovery in the total incorporation as well as in the size of HnRNA and poly (A) containing mRNA. Analysis of translation products by a two-dimensional procedure shows loss of some high molecular weight products in AFB₁-treated cells. At 24 h after AFB₁ treatment (hyperactive stage) there is a total recovery of activity. Also, several new translation products not detected in the control hepatocytes are synthesized at this stage. The hyperactive stage might represent gene-derepression or reprogramming of gene expression.