Inhibition of protein synthesis by N-methyl-N-nitrosourea in vivo

Abstract

1. The intraperitoneal injection of N-methyl-N-nitrosourea (100mg/kg) caused a partial inhibition of protein synthesis in several organs of the rat, the maximum effect occurring after 2-3h. 2. In the liver the inhibition of protein synthesis was paralleled by a marked disaggregation of polyribosomes and an increase in ribosome monomers and ribosomal subunits. No significant breakdown of polyribosomes was found in adult rat brains although N-methyl-N-nitrosourea inhibited cerebral and hepatic protein synthesis to a similar extent. In weanling rats N-methyl-N-nitrosourea caused a shift in the cerebral polyribosome profile similar to but less marked than that in rat liver. 3. Reaction of polyribosomal RNA with N-[(14)C]methyl-N-nitrosourea in vitro did not lead to a disaggregation of polyribosomes although the amounts of 7-methylguanine produced were up to twenty times higher than those found after administration of sublethal doses in vivo. 4. It was concluded that changes in the polyribosome profile induced by N-methyl-N-nitrosourea may reflect the mechanism of inhibition of protein synthesis rather than being a direct consequence of the methylation of polyribosomal mRNA.

On the Theory of Clonal Selection in Carcinogenic Transformation

“…The induction of a " transformed " state in vitro could be attributed to at least 3 cellular mechanisms: (1) direct transformation resulting from interaction with some critical target in the cell, (2) selection of pre-existing malignant cells or (3) activation of an oncogenic virus by the chemicals. MNU is known to alkylate nucleic acids (Swann and Magee, 1968;Rosenkranz, Bitoon and Schmidt, 1968) and cause inhibition of protein synthesis (Kleihues and Magee, 1973); methylation of DNA-guanine base, both in vivo and in vitro (Lawley, 1966;Schoental, 1967), might account for its mutagenic property in mammalian cells where it has been reported to cause single gene mutations (Kao and Puck, 1971) (Meyer et al, 1962) and a temperature sensitive variant, ts13, isolated by the methods described before (Naha, 1973c). These cell lines grow as monolayers to confluence and are strongly contactinhibited in culture.…”