Showing papers on "Demethylase published in 1970"

Mechanism of 3-methylcholanthrene-induced inhibition of dimethylnitrosamine demethylase in rat liver.

Abstract: Summary Previous studies on the inhibitory action of pretreatment of rats with 3-methylcholanthrene (MC) and other polycyclic hydrocarbons on the hepatic dimethylnitrosamine demethylase were extended. Experiments to test the presence of an endogenous inhibitor or inactivator of the demethylase in the cytoplasm of liver pretreated with MC yielded negative results. Kinetic studies showed considerable decrease in the Vmax and no alteration in the Km of the demethylase following MC administration. This suggests that the decrease of activity is due to a reduction of the amount of enzyme in microsomal preparations from hydrocarbon-pretreated rats. Phenobarbital inhibits dimethylnitrosamine demethylation, although to a lesser extent than MC. Prolonged repeated treatment of sexually immature female rats with high doses of 17α-methyltestosterone evokes no change in demethylase activity. MC brings about the same inhibition in young adult males and females, and this inhibition is quantitatively similar to that observed in immature male rats. When the hydrocarbon is administered to rats along with actinomycin D or puromycin, the inhibitory effects on demethylation are additive. This appears to rule out the possibility that MC acts at the same target as these antibiotics. The totality of the available data suggests that MC (and other polycyclic hydrocarbons) possibly turns off the gene(s) coding for dimethylnitrosamine demethylase.

Amino Acid Induction and Carbohydrate Repression of Dimethylnitrosamine Demethylase in Rat Liver

Abstract: Starvation of rats for 24 hr considerably enhances hepatic dimethylnitrosamine demethylase activity, and 3-methylcholanthrene pretreatment inhibits the enzyme in starved animals to the same extent as in fed animals. Determination of the kinetic constants following starvation revealed significant increase of the apparent Vmax indicating increase in the amount of demethylase. There was no significant change in the Km. Studies with actinomycin D provide strong support that starvation-induced increase is due to de novo protein synthesis, consistent with the observed increase in maximal velocity. Ingestion of glucose markedly inhibits demethylase activity while ingestion of casein alone stimulates it appreciably, in a manner analogous to such phenomena with a few other hepatic enzymes. These results and previous data suggest that the level of dimethylnitrosamine demethylase in liver is under the control of multiple regulatory factors.

Nickel Carbonyl Inhibition of Induction of Aminopyrine Demethylase Activity in Liver and Lung

Abstract: Summary Exposure of rats to nickel carbonyl, Ni(CO)4, in LD50 dosage inhibited the basal (noninduced) levels of hepatic aminopyrine demethylase activity. The maximum inhibition of hepatic aminopyrine demethylase occurred on the 2nd day after an injection of Ni(CO)4, and aminopyrine demethylase activity returned to normal levels by the 4th day after Ni(CO)4. Administration of Ni(CO)4 also inhibited hepatic aminopyrine demethylase activity in rats that had received daily injections of phenobarbital beginning 5 days before the Ni(CO)4. However, in the phenobarbital-treated rats, maximum inhibition of hepatic aminopyrine demethylase did not occur until the 5th day after Ni(CO)4 and aminopyrine demethylase activity did not return to normal levels until the 9th day after Ni(CO)4. These experiments and other related studies indicate that Ni(CO)4 inhibition of hepatic aminopyrine demethylase activity follows a distinctly different temporal sequence in noninduced and phenobarbital-treated rats. The mean activity of aminopyrine demethylase activity in rat lungs was increased 2 days after ingestion of phenothiazine. Exposure of rats to Ni(CO)4 inhibited the phenothiazine induction of pulmonary aminopyrine demethylase activity.

Induction of drug metabolism. IV. Relative abilities of polycyclic hydrocarbons to increase levels of microsomal 3-methyl-4-methylaminoazobenzene N-demethylase activity and cytochrome P1-450.

Abstract: Previous studies from this laboratory showed that the administration of 3-methylcholanthrene and 3,4-benzpyrene caused the formation of cytochrome P 1 -450, which differs from cytochrome P-450 in its substrate specificity, in the difference spectra it produces with ethyl isocyanide, and in its drug-binding properties. Six polycyclic hydrocarbons, previously shown to range in inductive capacities from no activity to very high activity, were administered to rats. The various degrees of induction of 3-methyl-4-methylaminoazobenzene N -demethylase that resulted were related directly to changes in ethyl isocyanide difference spectra and aniline binding difference spectra of microsomal hemoprotein, two measurements which reflect the presence of cytochrome P 1 -450. When a maximally stimulatory dose of a polycyclic hydrocarbon was given, it caused finite increases in microsomal 3-methyl-4-methylaminoazobenzene N -demethylase activity and cytochrome P 1 -450 content, whether it was a poor, intermediate, or potent inducing agent.

Dimethylnitrosamine Demethylase in Rat Liver

Abstract: SUMMARY Starvation of rats for 24 hr considerably enhances hepatic dimethylnitrosamine demethylase activity, and 3-methyl cholanthrene pretreatment inhibits the enzyme in starved animals to the same extent as in fed animals. Determination of the kinetic constants following starvation revealed signifi cant increase of the apparent Vmax indicating increase in the amount of demethylase. There was no significant change in the Km . Studies with actinomycin D provide strong support that starvation-induced increase is due to de novo protein synthesis, consistent with the observed increase in maximal velocity. Ingestion of glucose markedly inhibits demethylase activity while ingestion of casein alone stimulates it appreciably, in a manner analogous to such phenomena with a few other hepatic enzymes. These results and previous data suggest that the level of dimethylnitrosamine demethylase in liver is under the control of multiple regulatory factors.