Ethylmorphine N-demethylation Research Articles

The Effects of α,β-Unsaturated Aldehydes on Hepatic Thiols and Thiol-Containing Enzymes

The effects of series of α,β-unsaturated aldehydes on hepatic giutathione, cytochrome P450, and NADPH-cytochrome c reductase activity were compared with time. Male F-344 rats were dosed with muconaldehyde (36 μmol/kg), acrolein (89 μmol/ kg), crotonaldehyde (450 μmol/kg), or the saturated aldehyde propionaldehyde (89 μmol/kg) and terminated 0.5, 4, or 24 hr later. Acroiein or muconaldehyde reduced glutathione to 51 and 75% of controls, respectively, at 4 hr; glutathione returned control values at 24 hr. Only at 24 hr, acrolein, muconaldehyde, or crotonaldehyde decreased cytochrome P450 to 61, 71, and 67% of control values, respectively; ethylmorphine N-demethylation was decreased to a greater extent, i.e., to 35, 60, and 23% of controls. The reductase activity was unchanged at any time following the treatment with reactive aldehydes which were not hepatotoxic (as shown by glucose 6-phosphatase activity, histological changes, or serum enzymes). Propionaidehyde changed none of these activities. Acroiein (44.5 µmol/kg) given 4 hr prior to phenobarbital (50 mg/kg) for two consecutive days decreased the phenobarbital induction of cytochrome P450 45% of phenobarbital alone. This treatment also decreased the 2α, 2β, 6β, l6α, and 16β hydroxylation of testosterone as well as androstenedione formation showing effects on individual cytochrome P450 isozymes. NADPH-cytochrome c reductase induction was not decreased by this treatment, thus indicating that in vivo these changes are due to a mechanism other than generalized inhibition of protein synthesis.

Induction of rat hepatic mixed-function oxidases by acetone and other physiological ketones: their role in diabetes-induced changes in cytochrome P450 proteins.

1. To evaluate the role of ketone bodies in diabetes-induced changes in hepatic cytochrome P450 composition, rats were treated with acetone, 3-hydroxybutyrate or 1,3-butanediol. 2. Treatment with acetone enhanced the rat hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin, and the hydroxylation of p-nitrophenol, but had no effect on lauric acid hydroxylation and ethylmorphine N-demethylation. Neither 3-hydroxybutyrate nor 1,3-butanediol modulated the metabolism of the above substrates. 3. Immunoblot analysis of hepatic microsomal proteins revealed that treatment with acetone increased the apoprotein levels of P4501A2, P4502B1/2 and P4502E1. 4. It is concluded that acetone is responsible, at least partly, for the diabetes-induced increase in hepatic microsomal P4501A2, P4502B1/2 and P4502E1 proteins but does not mediate the increases in the P4503A1 and P4504A1 proteins. On the basis of work from our own and other laboratories a mechanism for the diabetes-induced changes in hepatic cytochrome P450 proteins is proposed.

Effects of ethinylestradiol and testosterone implants on hepatic microsomal cytochrome P450 monooxygenases of birth gonadectomized male and female Dark Agouti rats

Monooxygenases in the cytochrome P450 IIIA subfamily are induced by a number of their xenobiotic substrates and by testosterone, an endobiotic substrate of importance in their regulation. 17α-Ethinylestradiol (EE) is also metabolized by these enzymes and in this study Dark Agouti rats were used to examine the effects of subcutaneous implantation of controlled release silastic capsules containing EE to determine if this steroid also induces these enzymes. Data were compared with results obtained from equivalent groups of animals implanted with capsules containing testosterone propionate (TP). Liver microsomes prepared from male and female rats were used to identify intrinsic gender differences in the monooxygenases studied and gender differences in the responses to the implanted steroids were also determined. Effects due to imprinting of growth hormone secretion patterns were controlled by using male and female birth gonadectomized animals. Results obtained from groups with blank implants showed there were no effects due to the silastic implant material itself on the monooxygenases studied. The specific activities of erythromycin N-demethylation in liver microsomes of both EE and TP implanted male and female birth gonadectomized animals were enhanced relative to corresponding blank implanted controls consistent with both steroids having an effect to induce activity attributable to cytochrome P450 IIIA isoforms. Immunoinhibition studies using microsomes from EE treated female rats with erythromycin as substrate provided further evidence for this steroid having this induction effect. The specific activity of ethylmorphine N-demethylation was however not increased in microsomes prepared from the EE implanted female animals and was decreased in the corresponding male preparations. These findings distinguished the response to this steroid from that to TP and suggested induction by this estrogen of an isoform(s) having a more limited range of substrates than has characteristically been found in this subfamily. EE treatment also caused an increase in diazepam C 3 hydroxylase consistent with an effect to induce P450 IIIA activity but this was found only in microsomes from birth gonadectomized female animals. This was in contrast to the effect of TP treatment which produced increases in this monooxygenase in both male and female animals. Another gender specific effect of EE was a striking decrease in morphine N-demethylase activity seen only in birth gonadectomized male rats. This again contrasted with the effect of TP which caused a marked increase in this activity in liver microsomes of both male and female birth gonadectomized animals consistent with the proposal that testosterone is important in the regulation of this activity. EE also caused decreases in diazepam N-demethylase specific activity in both male and female rats and spectral evidence indicated that mechanisms other than heme alkylation may be responsible for the decreased activities of these monooxygenases.

The H +,K +-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole

The gastric acid antisecretory compound omeprazole (5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinylmethyl)-sulphinyl- 1 H-benzimidazole), a member of the new class of H +,K +-ATPase inhibitors, is known to interact with the metabolism of other drugs in vitro and in vivo. In this study, two other substituted benzimidazoles, pantoprazole (5-difluoromethoxy-2-(3,4-di-methoxy-2-pyridinylmethyl)-sulphinyl)- 1 H-benzimidazole) and lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylmethyl)-sulphinyl)-1 H-benzimidazole) are compared for their ability to inhibit cytochrome P450 dependent biotransformation in vitro with regard to three representative reactions: O-dealkylation of 7-ethoxycoumarin (EC), N-demethylation of ethylmorphine (EM) and hydroxylation of lonazolac (Lona). These reactions can be seen in microsomes from phenobarbital pretreated rats representing the cytochrome P450IIB1 subfamily. As shown in presence of known inhibitors of cytochrome P450, e.g. SK&F 525A, metyrapone, chlorpromazine and nitrendipine, different enzymes seem to be responsible for these three indicator reactions of the cytochrome P450IIB1 complex. These reactions are inhibited to a different extent by the three H +,K +-ATPase inhibitors. Pantoprazole shows the lowest inhibitory activity versus the three reactions ( K i , μmol/L): EC, 138; EM, 104; Lona, 128. A greater effect is observed with omeprazole: EC, 38; EM, 68; Lona, 20. Lansoprazole exceeds omeprazole in inhibiting the three cytochrome P450 dependent enzymes: EC, 17; EM, 34; Lona, 8. In microsomes from untreated rats with the predominant cytochrome P450IIA1 subfamily as well as in microsomes from isopropanol treated rats (induction of cytochrome P450IIE1) which catalyse only lonazolac hydroxylation to a detectable amount, the latter reaction was inhibited by pantoprazole with a somewhat lower K i of 77 whereas the values for omeprazole and lansoprazole remained unchanged in comparison to those found in microsomes from phenobarbital pretreated rats. The biotransformation rate of the substituted benzimidazoles themselves in microsomes from control and induced rats is lowest for pantoprazole followed by lansoprazole and omeprazole.

The influence of “essential” phospholipids (EPL) on phase-I- and phase-II-reactions and on the glutathione status in the liver of aging rats

"Essential" phospholipids (EPL; polyene-phosphatidylcholine) were administered orally to aging male rats in doses of 100 and 300 mg/kg b.wt. over 10 weeks. One and 7 days after the last treatment cytochrome P-450 concentration, epoxide hydrolase and glutathione-S-transferases were found to be unchanged, but ethylmorphine N-demethylation, ethoxycoumarin O-deethylation and UDP-glucuronosyltransferase activities were enhanced, as were the concentrations of both reduced and oxidized glutathione, the values being similar to those in young adult rats. These results are discussed in terms of an increase in endoplasmic reticulum membrane fluidity.

The influence of the radiation syndrome on cytochrome P450-dependent monooxygenation in rat liver

Cytochrome P-450 concentration and the monooxygenation activities of some cytochrome P-450 forms were determined in rat liver in the course of the acute radiation sickness. Ethylmorphine N-demethylation, ethoxycoumarin, ethoxyresorufin, and pentoxyresorufin O-dealkylation were used as indicator reactions. After radiation a distinct decrease in the hepatic biotransformation capacity can be observed, most pronounced at the climax of the radiation syndrome. Phenobarbital treatment (60 mg/kg b. m. at 3 consecutive days each) increases the concentration and the monooxygenase activities of some cytochrome P-450 forms. The degree of this induction effect is not altered at the third day after radiation, whereas at day 7 no significant inducibility can be observed.

Site-selective oxidation of strychnine by phenobarbital inducible cytochrome P-450.

The metabolism of strychnine was studied using liver microsomes of rats treated with phenobarbital or 3-methylcholanthrene (MC). The phenobarbital-treatment resulted in 7.9-fold and 4.8-fold increases in 2-hydroxylation and N-oxidation of strychnine, respectively. The formation of 16-hydroxystrychnine, strychnine 21,22-epoxide and 22-hydroxystrychnine was induced about 2-fold. MC-treatment resulted in only 1.4-fold induction of each oxidation activity. In addition, strychnine 2-hydroxylation activity was markedly induced in liver microsomes of phenobarbital-treated mice, guinea pigs, rabbits and dogs (2.5-10.5-fold). Induction of N-oxidation activity was also higher than that of the three other oxidation activities. A reconstituted system of strychnine metabolism using cytochrome P-450 isozymes, P-450I (P450IIB1) and P-450II (P450IIB2), purified from liver microsomes of phenobarbital-treated rats showed significantly high and selective activities towards 2-hydroxylation and N-oxidation of strychnine. This characteristic metabolism of strychnine appears to occur in common with interspecies P450IIB gene subfamily. The pH Optima of 2-hydroxylation and N-oxidation of strychnine were between 8.4 and 8.6 in the microsomes of phenobarbital-treated rats, while that of N-demethylation of benzphetamine, a typical substrate of phenobarbital-inducible cytochrome P-450, was between 7.4 and 7.6. In a reconstituted system with P-450I, strychnine oxidation was little affected by pH change, while benzphetamine N-demethylation activity was decreased in the alkaline side. Among several oxidations tested, only ethylmorphine N-demethylation underwent the same pH effect as did strychnine oxidation with the microsomes and reconstituted system.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of cytochrome P450III and P450IV family proteins in streptozotocin-induced diabetes

The effect of insulin-dependent diabetes on the hepatic microsomal activity of cytochrome P450III and P450IV family proteins was investigated in rats pretreated with streptozotocin. In order to discern between the effects of the diabetogen per se and those of the ensuing diabetes, streptozotocin-treated rats received in addition either nicotinamide to prevent the onset of diabetes or daily treatment with insulin to antagonize the effects of diabetes. Streptozotocin-treated rats displayed higher ethylmorphine and erythromycin N-demethylase activities and lauric acid hydroxylase activity. Increases were also detected immunologically by using monospecific polyclonal antibodies against the P450III and P450IV families. All effects were prevented by nicotinamide and effectively antagonized by insulin. In order to evaluate the role of the ketone bodies in the diabetes-induced increases in the above activities, rats were rendered hyperketonaemic by dietary administration of medium-chain triacylglycerols. These hyperketonaemic animals displayed high laurate hydroxylase activity and P450IV apoprotein levels, similar to those seen in the diabetic animals. Hyperketonaemia induced by dietary means caused a modest increase in the demethylation of erythromycin and had no significant effect on the N-demethylation of ethylmorphine. Furthermore, no marked increases were evident in the P450III apoprotein levels in the hyperketonaemic animals. It is concluded that insulin-dependent diabetes induces proteins of the P450III and P450IV families, and that the hyperketonaemia that accompanies diabetes is largely responsible for the changes in the latter family.

Influence of xenobiotics on drug metabolism and its sensitive detection

Biotransformation of drugs and other xenobiotics in the liver plays an important role intoxication and detoxication processes, i.e. changes in biotransformation activity have significant biological consequences. For that reason the determination of biotransformation activity is useful. The rate of some biotransformation reactions can be markedly changed by very small doses of xenobiotics. These changes may be used for the sensitive detection of the exposure to xenobiotics. Among biotransformation reactions cytochrome P-450-dependent monooxygenation is very important. It can be induced and inhibited by xenobiotics. Induction of P-450 forms can be detected by various methods, e.g. by using model reactions. Ethoxycoumarin O-deethylation, ethoxyresorufin O-deethylation, pentoxyresorufin O-depentylation and ethylmorphine N-demethylation are catalyzed at different P-450 forms, and their determination is described in detail.

Human fetal and adult liver metabolism of ethylmorphine: Relation to immunodetected cytochrome P-450 PCN and interactions with important fetal corticosteroids

The N-demethylation of ethylmorphine was studied in liver microsomes from human fetuses and adult patients as well as from human fetal adrenals and kidneys. Unexpectedly the reaction was catalysed at the same rate in fetal (42.3–1277.4 pmol/mg/min in 11 individuals) and adult microsomes (414–1617.8 pmol/mg/min in two individuals), which also had similar values of the apparent K m (1.50, 1.72 mM respectively) and V max (1.33,1.81 nmol/mg/min respectively) in studies of the enzyme kinetics. There was a close correlation ( r = 0.96) between the semiquantitative immunoblotting assessment of cytochrome P-450 HLp in fetal liver microsomes (with the use of a monoclonal antibody against pregnenolone-16-alpha-carbonitrile induced rat hepatic cytochrome P-450) and the catalytic activity. The fetal adrenal microsomal N-demethylation was only 11–30% of the hepatic activity when compared within three fetuses in which such a comparison was possible. No activity was measurable in the kidneys. Two drugs that are believed to be substrates of the cytochrome P-450 HLp were tested as inhibitors of the ethylmorphine N-demethylation in human fetal and adult liver microsomes and in rat liver microsomes. Midazolam was a potent inhibitor (100% at 0.4 mM) of the reaction in all specimens, whereas cyclosporin A inhibited the reaction clearly only in adult liver microsomes. Endogenous steroids of importance in the fetal circulation were also tested as inhibitors. Progesterone and dehydroepiandrosterone inhibited the reaction by 75–80% at a concentration of 0.4 mM, whereas pregnenolone and 17-alpha-hydroxy-progesterone were almost devoid of inhibitory potency. These results are of interest in the discussion about the physiological role of the human fetal cytochrome P-450 HLp which has an unprecedented relative abundance in the liver.

Influence of prenatal administration of cadmium on postnatal development and inducibility of hepatic monooxygenases in rats.

Cadmium inhibits hepatic monooxygenases in rats of different ages. But also in the offspring of dams which had received cadmium during pregnancy changes in biotransformation activities and their inducibilities could be observed. In the 30- and 60-day-old offspring a decrease in the inducibility of ethoxyresorufin O-deethylation by the specific inducer beta-naphthoflavone could be demonstrated, whereas cytochrome P-450 concentration, ethylmorphine N-demethylation and ethoxycoumarin O-deethylation were not influenced.

Purification and properties of cytochrome P-450 from liver microsomes of phenobarbital-treated marmoset monkeys ( Callithrix jacchus)

One form of cytochrome P-450 from phenobarbital-induced marmoset liver was purified to apparent electrophoretic homogeneity and compared with the major inducible form isolated from rat liver. Whereas spectral properties and molecular weights, as well as catalytic activities towards aminopyrine and ethylmorphine N-demethylation are quite similar, rates of O-dealkylation with enzymes from the two species are considerably different. While ethoxycoumarin deethylation for the marmoset cytochrome is about one-fortieth of that for the rat, ethoxyresorufin and even pentoxyresorufin dealkylations for the marmoset form are not detectable. By contrast, aldrin epoxidation as catalyzed by this cytochrome is about three times as high as that obtained from the rat.

Influence of glucocorticoids on the postnatal development of cytochrome P-450 in rat liver.

It is known that the activity of the cytochrome P-450 (P-450) monooxygenase system, which is responsible for detoxication as well as toxiciation of many xenobiotics, depends on age (Klinger 1982). Among other hormones, glucocorticoids may play a major role in the postnatal development of P-450-dependent xenobiotic metabolism. Jager-Roman et al (1982) found an increased theophylline metabolism in premature infants after prenatal dexamethasone administration. Dexamethasone treatment of 2-day-old rats caused a precocious development of hepatic P-450 concentration (Leakey and Fouts 1979). These effects need not be hormonal effects since dexamethasone induces the P-450PCN isozyme and this induction is probably not mediated by glucocorticoid receptors (Schuetz and Guzelian 1984). Therefore the effects were compared of dexamethasone, and pregnenolone 16α-carbonitrile (PCN) (without glucocorticoid action) on the postnatal development of ethylmorphine N-demethylation (EM- DM) and ethoxycoumarin O-deethylation (EC-DE) in rat liver. These reactions are catalyzed by different P-450 isozymes (Guengerich et al 1982).KeywordsPremature InfantGlucocorticoid ReceptorPostnatal DevelopmentMonooxygenase SystemDexamethasone AdministrationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Hepatic actions of levonorgestrel: Correlations between biochemical and morphological findings

The influence of the synthetic sexual steroid levonorgestrel (LN) on rat liver in various doses and at different structural levels was investigated. A slight reactive hepatosis was found by histological examination after administration of LN in a dose of 10 mg per kg body wt. The same dose caused exclusively distinct lesions of the mitochondria, however, only in centrilobular parenchymal cells, whereas in the periportal hepatocytes only the lipid droplet content appears somewhat elevated. LN decreased the total glutathione content of the liver. The mitochondrial glutathione was decreased more intensively. One mg/kg body wt. of LN decreased the cytochrome P-450 content, but 10 mg/kg body wt. increased ethyl-morphine N-demethylation and 7-ethoxycoumarin O-deethylation activities. Distinct correlations could be shown between the biochemical changes and the ultrastructural findings.

Influence of bipyridylium compounds on microsomal mixed-function oxidation activities.

The two principal bipyridyl herbicides, paraquat and diquat, were investigated for their influence on microsomal mixed-function oxidation (MFO) activities and on NADPH oxidation rates in lung, liver, and kidney preparations. In lung microsomal preparations, benzphetamine N-demethylation was found to be inhibited by paraquat and diquat in a concentration-dependent manner, but ethylmorphine N-demethylation was unaffected by these bipyridyls. In liver microsomal fractions, both benzphetamine and ethylmorphine N-demethylases were inhibited by paraquat and diquat. Neither bipyridyl affected MFO activity in kidney preparations. A kinetic investigation of the enzyme inhibition showed that only Vmax was affected by paraquat and diquat, providing the first evidence for noncompetitive inhibition by the bipyridyls. In all microsomal preparations, NADPH oxidation was stimulated significantly by paraquat and to an even greater extent by diquat in the absence or presence of benzphetamine or ethylmorphine. The influence of MFO substrates on the stimulation varied widely among the three organ systems. In lung, paraquat- or diquat-mediated stimulation of NADPH oxidation was equal in the absence of MFO substrates and in the presence of ethylmorphine, but the stimulation was increased in the presence of benzphetamine. Stimulation of NADPH oxidation by the bipyridyls, in liver as well as in kidney preparations, was equal in all situations in the absence of MFO substrates and in the presence of benzphetamine or ethylmorphine, although the quantity of this stimulation was greater in liver than in kidney fractions. It is apparent that the bipyridyls are potent stimulators of in vitro NADPH oxidation in microsomal preparations from several organs. The quantity of the NADPH oxidation stimulation seems to be a decisive factor in the inhibition of xenobiotic metabolism. Whether the stimulation of NADPH oxidation and the non-competitive inhibition of xenobiotic metabolism play a significant role in bipyridyl toxicity are under further investigation.

Purification and characterization of two forms of chicken liver cytochrome P-450 induced by 3,4,5,3',4'-pentachlorobiphenyl.

3,4,5,3',4'-Pentachlorobiphenyl (PenCB), one of the most potent 3-methylcholanthrene (MC)-type inducers of hepatic enzymes in animals, caused a remarkable induction of liver microsomal monooxygenases, particularly 7-ethoxyresorufin (7-ER) O-deethylase, benzo(a)pyrene (BP) 3-hydroxylase, and testosterone 16 alpha-hydroxylase in chickens, but not NADPH-cytochrome c(P-450) reductase and cytochrome b5. Two forms of cytochrome P-450 (P-450) in liver microsomes of PenCB-treated chickens were purified and characterized. The absorption maxima of the CO-reduced difference spectra of both enzymes (chicken P-448 L and chicken P-448 H) were at 448 nm. From the oxidized form of their absolute spectra, chicken P-448 L was a low-spin form and chicken P-448 H was a high-spin form. They had molecular masses of 56 and 54 kDa, respectively. In a reconstituted system, 7-ER O-deethylation, BP 3-hydroxylation, and testosterone 16 alpha-hydroxylation were catalyzed at high rates by chicken P-448 L but not by chicken P-448 H. Chicken P-448 L also catalyzed N-demethylation of aminopyrine, benzphetamine, and ethylmorphine with relatively low activity. On the other hand, chicken P-448 H functioned only in catalyzing estradiol 2-hydroxylation. These results were supported by an inhibition study of microsomal monooxygenases using an antibody against each enzyme. Immunochemical studies revealed that the enzymes differ from each other but are both inducible by PenCB-treatment. Chicken P-448 L and chicken P-448 H respectively comprise about 82 and 7% of the total P-450 content in chicken liver microsomes.

Inhibition of microsomal biotransformation by a series of nitrogen and oxygen heterocyclic histamine h 2-antagonists

A homologous series of potent, long-lasting thiazolo-pyrimidone-pyridine histamine H 2-antagonists were examined for their inhibitory effects on rat hepatic ethylmorphine N-demethylation. Inhibitory potency increased in the order: 2-pyridinyl < 3-pyridinyl < 4-pyridinyl histamine H 2-antagonist. Substitution ortho to the pyridine nitrogen decreased inhibitory potency. Hydroxylation of the pyridine heterocycle decreased inhibitory potency, whereas substituent electronic effects did not appreciably alter the inhibitory potency of these compounds. Antagonists containing oxygen heterocycles were moderately potent inhibitors compared to those containing unsubstituted pyridine as the heterocycle. A 3-(6-methylpyridine) histamine H 2-antagonist was shown to be a slightly more potent inhibitor of ethinamate metabolism than cimetidine in rats. However, unlike cimetidine, it did not inhibit the plasma half-life of antipyrine in dogs at doses that were equally efficacious in inhibiting gastric acid secretion.

Lack of hepatic microsomal metabolism of deoxynivalenol and its metabolite, DOM-1

Rat hepatic microsomal preparations were used to study the metabolism of deoxynivalenol (DON) and its metabolite 3α,7α,15-trihydroxytrichothec-9,12-dien-8-one (DOM-1). The N-demethylation of ethylmorphine was monitored to assess the viability of the mixed-function oxidase. DON was incubated with microsomes and an NADPH-generating system. Samples were removed from the incubation system and analysed for DON using an HPLC equipped with a UV detector. After incubation for 30 min, there was no evidence of disappearance of DON or of the presence of new metabolites; neither was microsomal NADPH oxidation altered by the addition of DON. Rat and pig hepatic microsomal preparations were used to assess DON glucuronidation, using p-nitrophenol disappearance to check the viability of the microsomal glucuronidating system. When DON was incubated with microsomes and 14C-labelled uridine 5′-diphosphoglucuronic acid, no radioactivity was detected in the TLC zone where the glucuronide was expected. Three rats and one pig were dosed orally with 2 mg DON/kg and samples of their urine and faeces were extracted and incubated with β-glucuronidase or with buffer only. No differences in DON or DOM-1 concentrations were detected between samples incubated with or without β-glucuronidase. These results suggest that DON was neither bioactivated to a more toxic product nor oxidized to a less toxic compound by the rat hepatic mixed-function oxidase system. Likewise, DOM-1 was not reactivated or metabolized by this system. Neither DON nor DOM-1 glucuronides were formed either in in vitro liver systems or in vivo.

Interaction of induction, ontogenetic development and liver regeneration on the monooxygenase level

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.

Experimental liver cirrhosis does not influence reproductive performance of female rats and development of hepatic biotransf ormation in their offspring

Experimental hepatic cirrhosis was produced in virgin female Wistar rats by thioacetamide (TAA) administration with the drinking water from the 4th up to the 6th month of life. Mating occurred 31 +/- 3 d after cessation of TAA treatment. At the time the body mass of cirrhotic rats was not different from that of untreated controls. Body mass gain during pregnancy, length of gestation, litter size and body mass of the newborns were not influenced by experimental cirrhosis. Lactation seems to be slightly decreased in TAA-dams in the first 5 postnatal days, reflected by lower growth rates of TAA- and control-pups nursed by TAA- in comparison to control-dams. Somatic development (body mass) and hepatic biotransformation (ethylmorphine N-demethylation and ethoxycoumarin O-deethylation) were not different in the TAA- and control-offspring up to adulthood. Liver mass was enhanced in TAA-offspring at birth, but not any longer in 10-d-old and older rats.