The metabolism of the anti-tumour agent 1(1-aziridinyl)- 2,4-dinitrobenzene (CB 1837).

1-(1-Aziridinyl)-2,4-dinitrobenzene (CB 1837) is the parent member of a series of nitrophenyla-ziridines having a highly specific action against the Walker tumour in the rat. CB 1837 was much less cytotoxic in vitro than was predicted on the basis of its antitumour activity in vivo, but its activity was enhanced in the presence of liver 9000-g supernatant and cofactors, which also converted it into a metabolite, 2-amino-1-(1-aziridinyl)-4-nitrobenzene. This metabolite was more active in the in vitro test than was CB 1837.CB 1837 is extensively metabolised in vivo by the rat, and the following urinary metabolites have been identified by mass spectrometry and quantitatively determined after administration of the tritium-labelled drug: 1-(2-chloroethyl)amino-2,4-dinitrobenzene and its 2-hydroxyethylamino analogue; 2,4-dinitroaniline: 2-amino-1-(1 -aziridinyl)-4-nitrobenzene,2-amino-1-(2-chloroethyl)amino-4-nitrobenzene and their respective N(2)-acetyl derivatives; and S-[N-(2,4-dinitrophenyl)-2-aminoethyl] mercapturic acid.     

Effects of purified and technical piperonyl butoxide on drug-metabolizing enzymes and ultrastructure of rat liver

Weanling male rats were fed technical grade piperonyl butoxide at dietary levels of 1000, 5000 and 10,000 ppm for 1, 4 and 8 weeks and 100 ppm for 1 week. Activities of hexobarbital oxidase, aniline hydroxylase, p-nitroanisole-demethylase, nitroreductase, glucuronyltransferase and P-450 content were increased 2- to 4-fold by 5000 or 10,000 ppm technical grade piperonyl butoxide. Liver weight and microsomal protein were increased a maximum of 50–70% by piperonyl butoxide. Electron microscopy showed enlargement and extensive proliferation of the smooth endoplasmic reticulum (SER) in liver parenchymal cells of rats fed 5000 or 10,000 ppm technical grade piperonyl butoxide. A dose of 1000 ppm produced minimal effects on liver weight, P-450, and glucuronyltransferase activity, but no effects of this dose could be detected on proliferation of the SER. Maximum induction of P-450 and the drug-metabolizing enzymes which require P-450 occurred after 1 week of exposure with all doses of piperonyl butoxide. In contrast, the effects of 10,000 ppm piperonyl-butoxide on liver weight, cellular hypertrophy and SER proliferation appeared greater after 8 weeks than after 1 week. No differences in the degree of SER proliferation could be detected after different lengths of exposure to 5000 ppm piperonyl butoxide. Glucuronyl transferase activity was induced maximally between 4 and 8 weeks at all dose levels. Purified and technical grade piperonyl butoxide (10,000 ppm) were equally effective in increasing liver drug-metabolizing enzymes and producing proliferation of the SER.