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1. The induction and inhibition of some biotransformation enzymes by valproate have been studied in hepatocytes isolated from rats treated with sodium valproate either i.p. or by subcutaneous implantation of osmotic pumps. 2. When valproate was given i.p., the cytochromes P-450 and b5, and aldrin epoxidase and glutathione S-transferase activities were significantly induced. 3. In contrast, valproate administered by osmotic pumps induced 7-ethoxycoumarin-O-deethylase activity, whereas aldrin expoxidase and glutathione S-transferase activities were significantly inhibited. At a valproate serum concentration of about 100 micrograms/ml for 2 weeks a significant induction of the cytochromes P-450 and b5 was observed. 4. Since there is a large difference between the half-lives of valproate in man and rodent, constant-rate delivery of valproate represents a better model for induction studies than i.p. injection.

Until now, no data are available concerning the biotransformation and toxicity of 2-methylpropene (or isobutene), a gaseous alkene widely used in industry (rubber, fuel additives, plastic polymers, adhesives, antioxidants). In this work, the biotransformation of 2-methylpropene (MP) has been studied, using total liver homogenates of mice, supplemented with a NADPH-generating system. In analogy to other olefins, 2-methylpropene is metabolized to its epoxide 2-methyl-1,2-epoxypropane (MEP), as proved by the identification by gas chromatography coupled with mass spectrometry. The epoxidation is cytochrome P-450 dependent, as shown by experiments in the absence of the NADPH-generating system and in the presence of various concentrations of metyrapone and SKF 525-A, two known inhibitors of the mono-oxygenases. A simple gas chromatographic headspace method has been developed for the quantitative determination of the epoxide formed. The formation of MEP is never linear in function of time and it reaches a maximum after 20 min. Thereafter is decreases continuously to undetectable levels. This observation can be explained by the immediate action of epoxide hydrolase and glutathione S-transferase, converting the epoxide to 2-methyl-1,2-propanediol and to the glutathione conjugate respectively. The involvement of both enzymes has been demonstrated by the addition of 3,3,3-trichloropropene oxide and indomethacin. These inhibitors of, respectively, epoxide hydrolase and glutathione S-transferase increase the epoxide formation in a significant way. The actual concentration of MEP is therefore not only dependent on its formation by cytochrome P-450 dependent mono-oxygenases, but also on its conversion by epoxide hydrolase and glutathione S-transferase, both very active in liver tissue.

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