Rats were subjected to cerebral compression ischaemia for 15 min and were subsequently recirculated with blood for periods up to 3 h. In viuo incorporation of intravenously administered ~-[l-'~CJvaline into total brain proteins was found to be severely inhibited (about 20% of controls) after 45 min of recirculation. After 3 h, protein synthesis had increased, the specific radioactivity of proteins then being about 40% of controls. The post-ischaemic inhibition of protein synthesis was accompanied by a breakdown in polyribosomes and a concomitant increase in ribosomal subunits. In vitro incorporation of ~-['~C]phenylalanine by a postmitochondrial supernatant system derived from animals subjected to 15 min ischaemia and 15 min recirculation was also severely reduced and showed, in contrast to control animals, no response to the addition of a specific inhibitor of polypeptide chain initiation (Poly (1)). Together with the in uioo accumulation of ribosomal subunits this indicates a block in peptide chain initiation during the early stages of recirculation.Polyribosomes from animals subjected to 15 min ischaemia without recirculation showed a normal rate of in oitro protein synthesis which was inhibited by Poly(1) to a similar extent as polyribosomes from control animals. These results suggest that the post-ischaemic inhibition in chain initiation develops during the early stages of recirculation rather than during the ischaemic period itself.

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The role of DNA alkylation by the neurooncogenic agent 3,3-dimethyl-1-phenyltriazene (DMPT) was investigated perinatally and in adult rats. Following a single subcutaneous injection of 14C-DMPT (100 mg/kg) on the 21 day of gestation, the concentration of methylated purines was similar in both fetal liver and brain whereas during postnatal growth this treatment resulted in an increasingly preferential methylation of liver DNA. In 30-day-old and adult rats the concentration of 7-methylguanine in liver was about 8 times higher in brain DNA, suggesting that during prenatal development both liver and brain DNA are transplacentally methylated by a proximate carcinogen produced by maternal organs. Multiple doses of 14C-DMPT (50 mg/kg) to adult rats led to a preferential accumulation of O6-methylguanine in cerebral DNA. This supports the hypothesis that the deficient repair excision capacity of the hypothesis that the deficient repair excision capacity of the central nervous system is a significant factor in the organ-specific carcinogenicity of DMPT and related carcinogens.

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Recent experiments are reviewed which indicate that O⁶-alkylation of guanine in nuclear DNA constitutes a promutagenic lesion possibly implicated in malignant transformation by monofunctional alkylating carcinogens. The differential capacity of various organs to enzymically excise O⁶-alkylguanine from their DNA seems to correlate with the organ specificity of the carcinogenic effect.

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