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Dimethylnitrosamine-induced Inhibition of Hepatic Protein Synthesis in Vitro and the Effect of Pretreatment with Cystamine or Pregnenolone-16-carbonitrile¹

Max-Planck-Institut für Hirnforschung, 5 Cologne 91, West Germany

Hepatic protein synthesis was investigated using a postmitochondrial supernatant system derived from the livers of rats that were given injections of a single dose of dimethylnitrosamine (DMN), 30 mg/kg. The time course and extent of DMN-induced inhibition in vitro were identical to those reported for the incorporation of amino acids into liver proteins in vivo, maximum inhibition being about 70% at 5 hr. Addition of specific inhibitors of chain initiation (polyinosinic acid and aurin tricarboxylic acid) to the postmitochondrial supernatant system from DMN-treated rats caused only a slight additional inhibition, indicating that DMN predominantly affects translation by a block of initiation. Treatment with cystamine prior to DMN administration completely abolished the depression of protein synthesis and reduced by more than 90% the methylation by [¹⁴C]DMN of purine bases in liver DNA. Pretreatment with pregnenolone-16-carbonitrile stimulated protein synthesis in controls but had no preventive effect in DMN-treated rats and did not reduce the extent of DNA alkylation in vivo.

¹ Supported by the Deutsche Forschungsgemeinschaft (K1 351/1).

² To whom reprint requests should be addressed.

³ Present address: International Agency for Research on Cancer, Lyon, France.

Received 5/ 1/75. Accepted 8/26/75.