Species and strain differences in the butylated hydroxytoluene (BHT)-producing induction of hepatic drug oxidation enzymes.
(9/13)
Five week-old, Wistar-JCL male and female rats and C57BL/6N male mice give a 0.5% butylated hydroxytoluene (BHT)-containing diet for 6 days produced a marked increase in hepatic weight and microsomal protein content. However, the augmentations of cytochrome P-450 content and drug oxidation activities were much more significant, i.e. 2.5-fold and more than three-fold increases were observed on a body weight basis, respectively. BHT-induced cytochrome P-450 cannot be distinguished from phenobarbital (PB)-induced cytochrome in many respects we have examined: i.e. 1) a broad substrate specificity; 2) absence of the blue shift in the CO-binding difference spectrum; 3) no rise in the peak height ratio of ethylisocyanide difference spectrum; 4) absence of alpha-naphthoflavone inhibition of p-nitroanisole demethylase activity; 5) marked increases of 50,000 and 54,000 molecular weight polypeptides in SDS-polyacrylamide gel electrophoresis. However, the induction of 46,000 molecular weight polypeptide by BHT in rats was more conspicuous than that by PB, and this induction was not observed in mice. In contrast to this marked induction, the administration of BHT to MC nonresponsive DBA/2N mice produced neither heptic enlargement nor induction of cytochromes, but did not produce an extremely high mortality. (+info)
Effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system.
(10/13)
We have examined the effect of dietary protein deficiency on rat hepatic drug-metabolizing enzyme system for a period of two months. Cytochrome P-450 and b5 contents in liver microsomes, which were plotted on semilogarithmic paper as a function of the time of deficiency, showed biphasical reductions during protein deficiency: rapid decreases in the first 3 weeks were followed by more gradual decreases. However, the three enzymatic activities examined, i.e. aminopyrine demethylase, aniline hydroxylase and p-nitroanisole demethylase, were not reduced at a uniform rate. In the earlier phase, activities of the former two enzymes were reduced more rapidly than that of the last phase. This biphasical and non-uniform reduction of enzymatic activities suggests the existence of two or more cytochrome P-450 subspecies in non-depleted male rats. Intraperitoneal administration of well-known environmental pollutants, polychlorinated dibenzofurans and biphenyls (100 micrograms and 100 mg/kg, respectively) to the depleted rats resulted in a marked induction of drug-metabolizing enzymes. However, as the deficiency became more severe (2 months), the induction declined to a considerable degree, especially in the case of polychlorinated biphenyl administration. (+info)
Effect of 2-aminonaphthalene on glutathione content and cytochrome P-450 p-nitroanisole O-demethylation activity in mouse liver.
(11/13)
Four days after single i.p. administrations of 2-aminonaphthalene to C3H mice, the liver content of reduced glutathione and the liver microsomal cytochrome P-450 O-demethylation activity were decreased. No changes were observed in oxidized glutathione. (+info)
Hepatic microsomal dealkylations. Inhibition by a tyrosine-copper (II) complex provided with superoxide dismutase activity.
(12/13)
The effect of a divalent copper-tyrosine complex has been evaluated in rat liver microsome-catalyzed dealkylations. The copper complex, which is provided with superoxide dismutase activity, inhibits at micromolar concentrations aminopyrine, p-nitroanisol, and 7-ethoxycoumarin dealkylations. It has also been found that cumene hydroperoxide-supported p-nitroanisol demethylation, the formation of a 440 nm species, and the formation of superoxide radicals are inhibited by the divalent copper complex. On the other hand, 3-chloroperbenzoic acid has been found to support a copper complex-insensitive 7-ethoxycoumarin dealkylation. Oxygen uptake by rat liver microsomes is also inhibited by the copper complex. The data support the concept that the copper complex acts as a superoxide dismutase at the level of a cytochrome P-450 intermediate species, liganded with superoxide anions. (+info)
Polychlorinated dibenzofurans--potent inducers of rat hepatic drug-metabolizing enzymes.
(13/13)
The effects of polychlorinated dibenzofurans (PCDFs), trace toxic contaminants of commercial polychlorinated biphenyl preparations (PCBs), on the induction of hepatic drug-metabolizing enzymes were studied in the rat. PCDFs were about a thousand times more potent than PCBs (Kanechlor-500) as inducers of cytochrome P-450. Rats given 10 microgram/kg of PCDFs intraperitoneally for 3 days showed significantly increased hepatic cytochrome P-450 levels. At the highest dose tested, 1000 microgram/kg, a two-fold increase of cytochrome P-450 and a three-fold increase of p-nitroanisole demethylase activity were observed. PCDFs and 3-methylcholanthrene had quite similar effects on microsomal drug-metabolizing enzymes. Both drugs increased p-nitroanisole demethylase activity strikingly and aniline hydroxylase activity moderately, but produced little change in aminopyrine demethylase activity. alpha-Naphthoflavone, which is known to be a specific inhibitor of aryl hydrocarbon hydroxylase induced by polycyclic aromatic hydrocarbons, inhibited at low concentrations p-nitroanisole demethylase activity of rats previously treated with both drugs. Further, both drugs increased the 455 nm to 430 nm peak ratios of ethyl isocyanide difference spectra. Following three daily doses of PCDFs (100 microgram/kg), cytochrome P-450 level and p-nitroanisole demethylase activity remained elevated for over 15 days, with a decrease to control levels after 30 days. Such indicates the slow excretion of PCDFs. (+info)