SHORT COMMUNICATION: The in vitro metabolic activation of the 11-trifluoromethyl analogue of the potent carcinogen 15, 16-dihydro-11-methyl-cyclopenta[a]-phenanthren-17-one to mutagens

A strongly electronegative, bay-region analogue of the potent carcinogen 15, 16-dihydro-11-methylcyclopenta[a]phenanthren-17-one, namely 15, 16-dihydro-11-trifluoromethylcyclopenta[a]phenanthren-17-one, is mutagenic to Salmonella typhimurium TA100. Also it is metabolized at the 1, 2- and 3, 4-positions in the A-ring as well as C-15 in the D-ring to give 3, 4-dihydroxy-3, 4, 15, 16-tetrahydro-11-trifluoromethyl-cyclopenta[a]phenanthren-17-one as the only mutagenic metabolite. In these respects its behaviour is closely similar to that of the 11-methyl compound, suggesting that the electronic nature of the bay-region substituent is rather less critical than its spatial configuration in influencing metabolism to genotoxic intermediates. It remains to be seen, however, whether the trifluoromethyl compound is also a carcinoge

A glucosinolate-rich extract of Japanese Daikon perturbs carcinogen-metabolizing enzyme systems in rat, being a potent inducer of hepatic glutathione S-transferase.

Purpose: Glucosinolates/isothiocyanates are an established class of naturally occurring chemopreventive agents, a principal mechanism of action being to limit the generation of genotoxic metabolites of chemical carcinogens, as a result of modulation of cytochrome P450 and phase II detoxification enzymes. The objective of this study was to assess whether a glucosinolate-rich extract from Daikon sprouts, containing glucroraphasatin and glucoraphenin, is a potential chemopreventive agent by modulating such enzymes in the liver and lung of rats. Methods: Rats were exposed to the glucosinolate-rich Daikon extract through the diet, at three dose levels, for 14 days, so that the low dose simulates dietary intake. Results: At the low dose only, a modest increase was noted in the hepatic dealkylations of methoxy-, ethoxy-, pentoxyresorufin and benzyloxyquinoline that was accompanied by elevated expression of CYP1 and CYP3A2 apoprotein levels. In lung, only a modest increase in the dealkylation of pentoxyresorufin was observed. At higher doses, in both tissues, these increases were abolished. At the same low dietary dose, the Daikon extract elevated markedly glutathione S-transferase activity paralleled by rises in GSTα, GSTμ and GSTπ protein expression. An increase was also noted in quinone reductase activity and expression. Finally, glucuronosyl transferase and epoxide hydrolase activities and expression were also up-regulated, but necessitated higher doses. Conclusion: Considering the ability of Daikon glucosinolates to effectively enhance detoxification enzymes, in particular glutathione S-transferase, it may be inferred that consumption of this vegetable may possess significant chemopreventive activity and warrants further evaluation through epidemiology and studies in animal models of cancer

The metabolism of some barbiturate drugs: Factors affecting the metabolism of barbiturates.

The ability of a compound to induce the rat hepatic microsomal drug metabolizing enzymes was investigated using a series of commonly prescribed barbiturates. The biological half-life of these barbiturates was also determined in the rat using a sensitive gas-liquid chromatographic method. It was found that inductive ability depends on rate of metabolism of the compound and therefore on its chemical properties. Evidence is presented supporting the theory that ethanol is not a substrate of the enzyme system known to detoxify a diversity of compounds. The effect of chronic and acute ethanol administration on the mixed-function oxidase is investigated. The metabolic interaction of ethanol with barbiturates is studied both in vivo and in vitro. Ethanol is shown to potentiate the inductive effect of the barbiturates. Possible mechanisms of interaction are discussed. The interaction of barbiturates with imipramine is examined in vivo and imipramine is shown to inhibit the metabolism of pentobarbitone. The importance of the allyl group in the chemical induction of porphyria is considered using a variety of allyl group containing compounds. Porphyrogenicity of a compound is compared with its ability to induce drug metabolism. It is shown that compounds increasing the level of cytochrome P-450 in the microsomes do not necessarily induce delta-aminolaevulinic acid synthetase and vice versa. Finally the use of formic acid vapour in the carrier gas in gas liquid chromatography is critically considered. Formic acid is shown to reduce adsorption of polar compounds on stationary phase of the column and thus improves the limit of quantitation. Evidence is presented for possible mechanisms

The metabolism of some barbiturate drugs: Factors affecting the metabolism of barbiturates.

The ability of a compound to induce the rat hepatic microsomal drug metabolizing enzymes was investigated using a series of commonly prescribed barbiturates. The biological half-life of these barbiturates was also determined in the rat using a sensitive gas-liquid chromatographic method. It was found that inductive ability depends on rate of metabolism of the compound and therefore on its chemical properties. Evidence is presented supporting the theory that ethanol is not a substrate of the enzyme system known to detoxify a diversity of compounds. The effect of chronic and acute ethanol administration on the mixed-function oxidase is investigated. The metabolic interaction of ethanol with barbiturates is studied both in vivo and in vitro. Ethanol is shown to potentiate the inductive effect of the barbiturates. Possible mechanisms of interaction are discussed. The interaction of barbiturates with imipramine is examined in vivo and imipramine is shown to inhibit the metabolism of pentobarbitone. The importance of the allyl group in the chemical induction of porphyria is considered using a variety of allyl group containing compounds. Porphyrogenicity of a compound is compared with its ability to induce drug metabolism. It is shown that compounds increasing the level of cytochrome P-450 in the microsomes do not necessarily induce delta-aminolaevulinic acid synthetase and vice versa. Finally the use of formic acid vapour in the carrier gas in gas liquid chromatography is critically considered. Formic acid is shown to reduce adsorption of polar compounds on stationary phase of the column and thus improves the limit of quantitation. Evidence is presented for possible mechanisms