ethylmorphine and 7-ethoxycoumarin

Four monoclonal antibodies (MAbs) to phenobarbital-induced cytochrome P-450 (PB-P-450) show different patterns of inhibition of PB-P-450 catalyzed aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin deethylase, benzphetamine demethylase and ethylmorphine demethylase. The inhibition constants vary depending on the individual monoclonal antibody and the individual substrate. Two of the four monoclonal antibodies completely inhibit the reduction of cytochrome P-450 by NADPH cytochrome c (P-450) reductase. The same cytochrome P-450 bound to carbon monoxide, however, can be reduced chemically by sodium dithionite in the presence of the monoclonal antibody. These data indicate that the two MAbs examined completely prevent electron transfer by NADPH cytochrome c (P-450) reductase. Substrate binding is partially inhibited by the monoclonal antibody. The type I substrate-binding spectrum of benzphetamine is inhibited more than the type II binding spectrum of aniline. The degree of inhibition of the substrate binding as indicated by the spectrum is less than that observed for the inhibition of catalytic enzyme activity by the monoclonal antibodies. The data indicate that each of the MAbs are directed toward epitopes on the cytochromes P-450 with different relationships to the active catalytic site.

Topics: Animals; Antibodies, Monoclonal; Benzphetamine; Coumarins; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Induction; Ethylmorphine; NADH Dehydrogenase; NADPH-Ferrihemoprotein Reductase; Phenobarbital; Rats; Rats, Inbred Strains

2/3 Hepatectomy (HX), but also sham operation (SO) decreased liver dry mass for the first 3-4 days after operation both in 10- and 60-day-old male Wistar rats, whereas body mass development was not altered. Both SO and HX decreased ethylmorphine N-demethylation (EN) and ethoxycoumarin O-deethylation (EO), but distinctly more pronounced after HX. In 10-day-old rats EN and EO were in the normal range 14 days after SO and HX. After 3 weeks EN even exceeded the control level. In 60-day-old rats SO alone resulted in decreased EN and EO even 3 weeks after operation. Compared with SO-controls EN was lower but EO was in the same range in HX rats 14 days after operation. Neither in 10- nor in 60-day-old rats inducibility by phenobarbital (PB) could be demonstrated 24 h after HX with cytochrome P-450 concentration (P-450), EN and EO as parameters. But inducibility by betanaphthoflavone (BNF) was significant for P-450, EN and EO in 10-day-old rats and also for P-450 and EO in 60-day-old rats. In the young adult rats EN was depressed by BNF. In rats 10 days old at HX inducibility by PB was highest 3-7 days after HX, but inducibility by BNF after 14 days. In 60-day-old rats inducibility by PB was highest for EO 1 day after HX. These results indicate that ontogenetic development can be enhanced by induction, that during development regeneration can be superimposed and both induction and regeneration can superimpose ontogenetic development. During these processes different monooxygenases are under differential control.

Topics: Age Factors; Aging; Animals; Benzoflavones; beta-Naphthoflavone; Body Weight; Coumarins; Cytochrome P-450 Enzyme System; Enzyme Induction; Ethylmorphine; Hepatectomy; Liver; Liver Regeneration; Male; Phenobarbital; Rats; Rats, Inbred Strains

After a 3-day treatment with T3 the ethylmorphine N-demethylation rate was diminished in 10- to 60-day-old rats, whereas the ethoxycoumarin O-deethylation rate was distinctly enhanced in some age-groups, particularly in 33-day-old rats. P-450 concentration was decreased in young rats and not changed in 60-day-old ones. Phenobarbital administration enhanced the rate of both reactions and P-450 concentration in all age-groups. This treatment significantly attenuated the T3 effects on P-450 concentration and ethylmorphine N-demethylation. beta-Naphthoflavone induced ethoxycoumarin O-deethylation and P-450 concentration in all age-groups. Compared with non-induced animals, the T3 effects on ethoxycoumarin O-deethylation (increase) and ethylmorphine N-demethylation (decrease) were more distinct, whereas P-450 concentration was scarcely influenced by T3. Age-differences in T3 actions were generally diminished by inducers.

Topics: Age Factors; Animals; Benzoflavones; beta-Naphthoflavone; Biotransformation; Coumarins; Cytochrome P-450 Enzyme System; Ethylmorphine; Liver; Male; Phenobarbital; Rats; Rats, Inbred Strains; Triiodothyronine