Differential effects of aging on hepatic microsomal monooxygenase induction by phenobarbital and β-naphthoflavone

The influence of aging on hepatic microsomal monooxygenase induction by phenobarbital (PB) or β-naphthoflavone (BNF) was investigated in male Fischer 344 rats maintained in a constant environment. PB-induced increases in microsomal cytochrome P-450 content and NADPH-cytochrome c reductase activity were similar in rats aged 3–5 months (young-adult) and 24–25 months (old), but increases in benzephetamine N-demethylase activity were markedly diminished in the old rats. Separation of hepatic microsomal proteins by sodium dodecylsulfate gel electrophoresis demonstrated that aging decreased the induction by PB of a polypeptide with a molecular weight of 52,500. BNF-induced increases in microsomal cytochrome P-450 and nitroanisole O-demethylase activity were greater in old than in young-adult rats, and BNF induction of 55,000 and 57,000 molecular weight microsomal polypeptides was increased slightly in livers from old rats. The results indicate that age-related effects on monooxygenase induction vary with different inducers of the hepatic microsomal enzyme system.     

Cytochrome P-450-dependent nicotine oxidation by liver microsomes of guinea pigs. Immunochemical evidence with antibody against phenobarbital-inducible cytochrome P-450

When guinea pigs were treated with phenobarbital (PB), the specific activity of liver microsomal nicotine oxidase increased by 42%. PB-inducible cytochrome P-450 (PB-P-450) was purified to homogeneity from liver microsomes of PB-treated guinea pigs. Purified PB-P-450 catalyzed nicotine oxidation when reconstituted with NADPH-P-450 reductase and phospholipid system. Antibody prepared against the purified PB-P-450 formed single precipitation lines with both purified PB-P-450 and microsomal components in livers of PB-treated guinea pigs, and both precipitation lines fused. The antibody against PB-P-450 strongly inhibited nicotine oxidation in the reconstituted system. The antibody also inhibited liver microsomal nicotine oxidase activities in PB-treated and untreated guinea pigs by about 30% and less than 5% respectively. About 45% of total P-450 in liver microsomes of PB-treated guinea pigs was precipitated by the antibody. These results show that PB-P-450 participates in liver microsomal nicotine oxidation in PB-treated guinea pigs but not in untreated control animals.     

Differential effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism in the rat

The effects of chronic ethanol feeding on cytochrome P-448- and P-450-mediated drug metabolism have been studied both in vivo and in vitro in the rat, using caffeine, phenacetin, antipyrine and aminopyrine as test substrates. N-Demethylation of aminopyrine (P-450 mediated) was increased both in vivo and in vitro in rats after chronic ethanol feeding (P < 0.05) whereas in vivoN-demethylation of caffeine and O-dealkylation of phenacetin (P-448 mediated) were unchanged in the same animals. N-rmDemethylation of antipyrine was increased by both phenobarbital and 3-methylcholanthrene pretreatment and by chronic ethanol feeding (P < 0.05), possibly due to cytochrome P-450 induction. Furthermore, the Michaelis affinity constants. K_m, for hepatic microsomal aminopyrine N-demethylase and antipyrine N-demethylase were lower in chronic ethanol-fed animals (P < 0.05), suggesting a qualitative change in the enzymes resulting in greater substrate affinity. These findings suggest a differential effect of chronic ethanol feeding on the induction of cytochrome P-450- and cytochrome P-448-mediated drug metabolism, with a greater effect on the former microsomal system.     

Species differences in stimulation of intestinal and hepatic microsomal mixed-function oxidase enzymes

The effect of intraperitoneal (i.p.) administration of phenobarbital (PB) or 3-methylchol-anthrene (3-MC) on some mixed-function oxidase (MFO) enzymes was studied in small intestine and liver of male rats, mice, guinea pigs and rabbits. PB treatment enhanced intestinal and 7-ethoxycoumarin deethylase activities in the mouse and rat, whereas benzo[a]pyrene hydroxylase (AHH) activity was increased only in the mouse. Ethylmorphine demethylase and aniline hydroxylase activities in small intestine were not stimulated by PB in any species. Administration of 3-MC increased the activity of intestinal AHH in rat, mouse and guinea pig, but intestinal 7-ethoxycoumarin deethylase activity was elevated only in the rat. The guinea pig and mouse intestinal ethoxycoumarin deethylase activity was inhibited by 3-MC treatment. None of the enzymes tested in rabbit intestine was induced by PB or 3-MC. The hepatic activities of ethylmorphine demethylase, aniline hydroxylase, 7-ethoxycoumarin deethylase and AHH, and the cytochrome P-450 content were increased by PB in all species. In contrast, 3-MC enhanced hepatic aniline hydroxylase and AHH activities in rats, mice and guinea pigs, and hepatic 7-ethoxycoumarin deethylase activity in mice and rats. In rabbits, these hepatic enzymes were inhibited by 3-MC pretreatment. The hepatic cytochrome P-450 absorption spectra was shifted to 448 nm in all species. These results suggest that there are differences in induction of intestinal and hepatic MFO enzymes which are influenced by the type of inducing agent, substrate and animal species used.     

Induction of drug metabolism. VI. Effects of phenobarbital and 3-methylcholanthrene administration on N-demethylating enzyme systems of rough and smooth hepatic microsomes

The induction of the microsomal hemoproteins, cytochromes P-450 and Pi-450, and of N-demethylase activities in hepatic microsomal subfractions from rats were studied at various times after administration of phenobarbital or 3-methylcholanthrene. After a single dose of phenobarbital, N-demethylase activity and cytochrome P-450 levels increased initially only in rough microsomes (RER) whereas a single dose of 3-methylcholanthrene caused almost simultaneous increases of the two enzymes in both RER and smooth microsomes (SER). The increases in N-demethylase activities during this early period of induction by 3-methylcholanthrene were paralleled by a change in P-450 hemoprotein from cytochrome P-450 to cytochrome P₁-450 in both microsomal subfractions, but the total amount of P-450 hemoprotein remained essentially unchanged. These results add to existing evidence that phenobarbital and 3-methylcholanthrene produce their inductive effects by different mechanisms and raise the possibility that cytochrome P₁-450 may be synthesized in both RER and SER.     

The effect of 3-methylcholanthrene on urinary 6 beta-hydroxycortisol excretion and hepatic enzyme activity in the marmoset monkey (Callithrix jacchus)

The effect of 3-methylcholanthrene treatment on the urinary excretion of 6β-hydroxycortisol and hepatic enzyme activity was investigated in the marmoset monkey (Callithrix jacchus). 3-Methylcholanthrene increased cytochrome P-448 content, NADPH cytochrome-c reductase activity, 7-ethoxy-coumarin O-deethylase activity and ethoxyresorufin O-deethylase but did not affect aminopyrine N-demethylase activity. This induction profile is qualitatively similar to that previously reported for the rat. There was no change in the ratio of urinary 6β-hydroxycortisol to 17-hydroxycorticosteroids. The pattern of response to 3-methylcholanthrene indicates that cortisol 6β-hydroxylase activity is not associated with induction of hepatic cytochrome P-448.     

Effects of vitamin A deficiency on hepatic and extrahepatic mixed-function oxidase and epoxide-metabolizing enzymes in guinea pig and rabbit.

Male guinea pigs and male rabbits were fed a vitamin A deficient diet for 9 weeks and for 12 weeks respectively. Hepatic levels of vitamin A were significantly reduced in the vitamin A deficient animals. The activities of some xenobiotic-metabolizing enzymes were measured in the liver, lung and small intestine. Aryl hydrocarbon hydroxylase, aniline hydroxylase, and 7-ethoxycoumarin deethylase activities were decreased in the vitamin A deficient guinea pig liver. However, in the guinea pig small intestine, aniline hydroxylase, 7-ethoxycoumarin deethylase, aminopyrine demethylase, and aryl hydrocarbon hydroxylase specific activities were increased. In rabbits, vitamin A deficiency decreased hepatic aniline hydroxylase and 7-ethoxycoumarin deethylase activities but increased intestinal aminopyrine demethylase activity. Enzyme activities in lung were not altered by vitamin A deficiency in guinea pig or rabbit. Microsomal epoxide hydrase and microsomal supernatant glutathione S-transferase activities in the three tissues of both species were not altered by vitamin A deficiency.     

Effects of dietary pectin and cellulose on hepatic and intestinal mixed-function oxidations and hepatic 3-hydroxy-3-methylglutaryl-coenzyme a reductase in the rat

The aim of this study was to determine if feeding dietary fiber (cellulose or pectin) to male rats could influence hepatic and intestinal mixed-function oxidation. We simultaneously compared hepatic drug-oxidizing activity with the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for cholesterol biosynthesis. Three groups of six animals were fed a purified diet containing by weight either 10.4% cellulose or 10.4% pectin, or a standard cereal-based diet containing 4.5% crude fiber; the caloric contributions by carbohydrate, protein and fat in the three diets were similar. In the cellulose-fed rats, the hepatic microsomal cytochrome P-450 content and the activities of ethylmorphine N-demethylase and aniline hydroxylase were significantly lower when compared with those of rats fed pectin or the cereal-based diet. The hepatic microsomal cytochrome P-450 content and the activities of ethylmorphine N-demethylase and aniline hydroxylase were similar in the pectin-fed and cereal diet-fed rats. Hepatic HMG-CoA reductase activity, hepatic microsomal cytochrome b₅ content, and intestinal benzo[a]pyrene hydroxylase activity were comparably lower in rats fed the purified diet with either dietary fiber when compared to those fed the cereal diet. It is concluded that dietary pectin and cellulose exert distinctly different influences on the hepatic microsomal mixed-function oxidase system for drug metabolism, but not on liver cholesterol synthesis or intestinal benzo[a]pyrene hydroxylation, suggesting that different physiological mechanisms control these enzyme systems.     

Induction of renal and hepatic mixed function oxidases in the hamster and guinea pig

A marked species difference exists in the induction of renal and hepatic mixed function oxidase (MFO) activity between rats and rabbits. However, little is known about MFO induction in these organs from other laboratory animals. Male Golden Syrian hamsters and male Hartley guinea pigs were administered phenobarbital (PB) or beta-napthoflavone (BNF) at 70 and 40 mg/kg, respectively, as daily i.p. injections for 4 days. Polybrominated biphenyl (PBB) (Firemaster BP-6) was given as a single i.p. injection (50 mg/kg). Hamster hepatic microsomal ethoxyresorufin-O-deethylase (EROD) and benzphetamine-N-demethylase (BPND) were selectively induced by BNF and PB, respectively. PBB administration induced both hamster hepatic EROD and BPND. In contrast, hepatic microsomal MFO activity from the guinea pig was inducible by PB, PBB and BNF. Renal microsomal MFO activity in both species was inducible by BNF and PBB as arylhydrocarbon hydroxylase and EROD were induced approximately 10-fold. On the other hand, hamster BPND was induced by PB whereas guinea pig MFO activity was unaffected. Total renal cytochrome P-450 content was not affected by any of these inducers in either species. These data demonstrate selective patterns of induction in both hamster and guinea pig liver and kidney suggesting the involvement of multiple forms of cytochrome P-450.     

Heme oxygenase activity, drug metabolism, amd ascorbic acid distribution in the livers of ascorbic acid-deficient guinea pigs.

The influence of ascorbic acid (AA) on microsomal heme oxygenase (MHO) (EC 1.14.99.3). drug metabolism and AA distribution was studied in livers and liver cytosols isolated from guinea pigs. Aminopyrine N-demethylase and cytochrome P-450 content were examined in guinea pigs on days 0,6,12 and 19 after being placed on a basal diet deficient in AA. Plasma AA seems to reflect total liver AA; however, AA from the liver cytosol (100,000 g soluble fraction) component decreased at a slower rate than total liver AA as deficiency progressed. The decrease in hepatic aminopyrine N-demethylase and in cytochrome P-450 content was related to the decrease in cytosolic AA. Perfusion of livers from guinea pigs not depleted of AA resulted in a 71 per cent loss of extracellular AA. Liver perfusions also resulted in 26.2 and 16.0 per cent decreases in cytochrome P-450 content from AA-deficient and AA-supplemented guinea-pigs (25 mg/100g) respectively. These data suggest that a labile soluble pool of AA may have some influence on cytochrome P-450 content and drug metabolism. MHO activity was decreased significantly (P < 0.05) in the livers from AA-deficient guinea pigs compared to AA-supplemented guinea pigs. In a separate experiment, guinea pigs were given either the basal diet alone or the basal diet and either 1 or 50 mg AA/100 g for 28 days. MHO activity was found to increase significantly with increasing doses of AA (P < 0.005). These results suggest a dose-related dependence of MHO on AA and that AA deficiency does not produce an increase in hepatic heme catabolism via increased MHO activity.     

Species differences in the substrate specificity of hepatic cytochrome P-448 from polycyclic hydrocarbon-treated animals.

The in vitro effects of α-naphthoflavone on four hepatic mono-oxygenase activities associated with aromatic hydrocarbon responsiveness in the mouse (aryl hydrocarbon hydroxylase, 2-acetylamino-fluorene N-hydroxylase, biphenyl 2-hydroxylase, and biphenyl 4-hydroxylase) were investigated before and after methylcholanthrene treatment of C57BL/6N and DBA/2N mice, rats, hamsters, guinea pigs and rabbits. The electrophoretic pattern of cytochrome P-450 subunits and reduced CO-hemoprotein difference spectra of the microsomal fractions were also studied. Pretreatment of animals with methylcholanthrene caused: (1) a 1.5 to 2 mm hypsochromic shift in the Soret peak of the reduced hemoprotein-CO complexes in liver microsomes from a C57BL/6N mouse, rat, hamster and rabbit; a 0.5-nm hypsochromic shift in the guinea pig and no shift in the DBA/2N mouse; and (2) an increase in cytochrome P-450 apoproteins of the following molecular weights on sodium dodecyl sulfate-polyaerylamide gel electrophoresis: 54,000 and 55,000 in the C57BL/6N mouse; 48,000, 54,000 and 55,000 in the rat; 49,000 and 54,000 in the hamster; and 54,000 and 57,000 in the rabbit; a small increase in the 54,000 band was seen in the DBA/2N mouse and no increase in the guinea pig. In vitro addition of α-naphthoflavone selectively inhibited all four mono-oxygenase activities from the methylcholanthrene-treated C57BL/6N mouse, rat and hamster; 2-acetylaminofluorene N-hydroxylase and biphenyl 4-hydroxylase activities in the rabbit; and aryl hydrocarbon hydroxylase, 2-acetylaminofluorene N-hydroxylase and biphenyl 4-hydroxylase activities in the guinea pig. The addition of α-naphthoflavone enhanced the activities of aryl hydrocarbon hydroxylase and biphenyl 2-hydroxylase in liver microsomes from both control and methylcholanthrenetreated rabbits, but only biphenyl 2-hydroxylase activity was increased in the guinea pig: the activitity of 2-acetylaminofluorene N-hydroxylase was increased in both control and methylcholan-threne-treated DBA/2M mice, but only in the control C57BL/6N mouse. These data indicate that hepatic cytochrome P-448 is composed of multiple cytochromes, which differ among animal species, each catalyzing different mono-oxygenase activities.     

Dietary ascorbic acid and hepatic mixed function oxidase activity in the guinea pig

Studies were carried out to characterize the response of hepatic mixed function oxidase (MFO) activity to chronic ascorbic acid deficiency and excessive ascorbic acid intake in the guinea pig. When guinea pigs were fed excessive ascorbic acid, there was a small increase in hepatic cytochrome P-450 which was unaccompanied by any alteration in drug-metabolizing enzyme activity. Similarly, induction of MFO activity by phenobarbital was not modified by excessive ascorbic acid administration. Chronic ascorbic acid deficiency resulted in depressed metabolism of aniline, aminopyrine, ethoxycoumarin and benzphetamine, but not of ethylmorphine, in comparison with animals fed diets containing control and/or excessive amounts of ascorbic acid. In contrast to the metabolism of all drugs studied, the 7 alpha-hydroxylation of cholesterol was depressed by both inadequate and excessive vitamin C intake, demonstrating the unique sensitivity of cholesterol 7 alpha-hydroxylase to dietary ascorbate.     

Effect of riboflavin deficiency on phenobarbital and 3-methylcholanthrene induction of microsomal drug-metabolizing enzymes of the rat

The effect of riboflavin deficiency on the induction of hepatic microsomal enzymes by phenobarbital and 3-methylcholanthrene has been investigated. A decrease in microsomal flavin levels of 56 per cent was associated with a decrease in NADPH cytochrome c reductase (52 per cent), azoreductase (71 per cent) and benzpyrene hydroxylase (74 per cent). Microsomal cytochrome P-450 content and aminopyrine demethylase were not significantly affected by flavin deficiency. Phenobarbital or 3-methylcholanthrene pretreatment did not affect hepatic microsomal flavin levels in normal or deficient animals. In flavin-deficient animals, phenobarbital pretreatment significantly increased cytochrome c reductase, cytochrome P-450 content, aminopyrine demethylase and azoreductase. Thus the carbon monoxide-sensitive pathway (cytochrome P-450 mediated) of azoreductase was essentially unaffected by flavin deficiency. In deficient animals, the carbon monoxide-insensitive microsomal azoreductase pathway (non-cytochrome P-450 mediated) normally induced by 3-methylcholanthrene was unaffected. Thus, induction of azoreductase by 3-methylcholanthrene was found to be flavin dependent. However, 3-methylcholanthrene did increase cytochrome P-450 content and benzpyrene hydroxylase in flavin-deficient animals. The induction of benzpyrene hydroxylase by 3-methylcholanthrene increased with increasing microsomal flavin content. Part of the mechanism of azoreductase induction by 3-methylcholanthrene was due to an induced change in the structure or composition of microsomal flavoprotein. This interpretation is supported by the findings that: (1) induction by 3-methylcholanthrene in riboflavin-deficient rats required a minimal flavin level, (2) increased enzyme activity was not compensated by an increase in microsomal flavin and (3) induction by 3-methylcholanthrene augmented FMN-stimulation of microsomal azoreductase in vitro.     

Hepatic drug metabolism after phenobarbital and diphenylhydantoin administration in the rat--influence of vitamin D3 status.

Measurements of aniline hydroxylation, aminopyrine N-demethylation and cytochrome P-450 content after a 3-week treatment with phenobarbital (PB), diphenylhydantoin (DPH) or a combination of the two drugs were undertaken during normal vitamin D status (D +) and vitamin D deficiency (D ?) with or without vitamin D₃(D₃) supplementation. Serum calcium concentrations were reduced after D deprivation but responded by a significant increase toward normal values to a single pharmacological dose of D₃. Serum phosphorus concentrations were also slightly raised by the supplementation. Even in the presence of higher cytochrome P-450 content in D ? rats, aniline hydroxylase and aminopyrine N-demethylase activities were lower in D ? than in D + animals. These two enzymatic parameters, as well as cytochrome P-450 content, were increased by anticonvulsant (ACV) drug treatment regardless of the D nutritional status. The in vivo hexobarbital sleeping time was shortened by ACV drugs but the sleeping time tended to be longer in D ? than in D + rats. Supplementation with 1000 I.U. of D₃, lowered aniline hydroxylase activity both in D + and D? animals; the supplementation had no effect on aminopyrine N-demethylase activity in D + animals but had an inhibitory effect after PB and a stimulatory effect after DPH treatment in D? animals. Cholecalciferol supplementation lowered cytochrome P-450 content toward normal values in D? rats while it had no effect in D + animals. These observations suggest that (1) PB and DPH pretreatment do not alter the normal response of serum calcium and phosphorus to a single pharmacological dose of D₃; (2) in a state of vitamin D deficiency accompanied by hypocalcemia, the inducing capacity of PB and DPH on the liver mixed function oxidase system is not lost; (3) under certain circumstances, vitamin D₃, can influence the catalytic activity of the mono-oxygenase complex; (4) cytochrome P-450 is influenced by vitamin D deficiency and/or changes in extracellular calcium but the forms induced by PB and DPH may not necessarily be the ones specifically involved in vitamin D metabolism.     

In vivo and in vitro effects of caffeine on hepatic mixed-function oxidases in rodents and chicks

Administration of caffeine, ip 100 mg/kg/day for 1–5 days, to adult male rats resulted in a significant increase in hepatic cytochrome P-450 and b₅ concentrations and in cytochrome c reductase aminopyrine N-demethylase and acetanilide hydroxylase activities. No change was seen in relative liver weight but microsomal protein content was increased after treatment for 1 day and decreased after treatment of 3 ot 5 days. In adult rats given 25, 100 or 150 mg caffeine/kg for 3 days. maximum stimulation of mixed-function oxidases was seen with the 100-mg/kg dose. Caffeine treatment (100 mg/kg for 3 days) increased relative liver weight in female guinea-pigs and decreased it in chicks and female mice, and decreased microsomal protein content in male mice, female guinea-pigs and young rats, and increased it in chicks. A significant increase in hepatic cytochrome P-450 content was seen in all species studied. Cytochrome b₅ content was increased in chicks and young rats, while cytochrome c reductase activity was increased in male and female mice, young rats and chicks and decreased in female guinea-pigs. Aminopyrine N-demethylase activity was increased in young rats and female guinea pig, and acetanilide hydroxylase was increased in all test species except male mice. In vitro addition of 2.5 mM-caffeine to microsomal incubations from untreated rats, guinea pigs, mice and chicks inhibited aminopyrine N-demethylase activity, athough only to a significant extent in male mice; addition of caffeine to incubations containing microsomes from caffeine-treated animals produced significant inhibitiobn of aminopyrine N-demethylase activity in microsomes from adult and young rats and female guinea-pigs. Aminopyrine N-demethylase inhibition did not increase concentration of added caffeine, although acetanilide hydroxylase activity was progressively inhibited in the microsomal incubates from both control and caffeine-treated animals.     

Mixed-function oxidase system induction and propylene hepatotoxicity

Propylene is hepatotoxic to male Charles River COBS Sprague-Dawley rats pretreated with polychlorinated biphenyls (PCB: Aroclor 1254). Four-hour inhalation exposure to 50,000 ppm propylene increased liver weight/body weight ratios and elevated serum enzyme activities in PCB-pretreated animals. Hepatic microsomal cytochrome P-450 content of PCB-pretreated rats dropped profoundly during propylene exposure and remained depressed for at least 24 h. In addition, PCB-pretreated, propylene-exposed rats exhibited a decrease in the specific activity of hepatic microsomal aniline hydroxylase. However, there was no change in activities of either hepatic microsomal aminopyrine demethylase or glucose-6-phosphatase. Propylene exposure of rats pretreated with beta-naphthoflavone (BNF), phenobarbital (PB), or a mixture of BNF and PB was not hepatotoxic. However, there was, in these animals, a substantial decline in hepatic microsomal cytochrome P-450 levels 24 h after the start of propylene exposure. Hence, the propylene-dependent process resulting in hepatic cytochrome P-450 destruction is qualitatively or quantitatively different from the process that causes acute hepatotoxicity. Preexposure fasting had no effect on the hepatotoxicity resulting from a 4-h exposure of PCB-pretreated rats to 50,000 ppm propylene. Administration of SKF-525A to PCB-pretreated rats immediately prior to propylene exposure completely prevented elevations in serum enzyme activities and liver weight/body weight ratios. In vitro incubation of hepatic microsomes prepared from either BNF-, PB-, or PCB-pretreated rats with an atmosphere of 20% propylene/80% air produced in NADPH-dependent decrease in cytochrome P-450 content. These results suggest that PCB pretreatment is a prerequisite for propylene hepatotoxicity in the rat. Cytochrome P-450-dependent bioactivation of propylene is associated with this hepatotoxicity, but further studies are needed to characterize the mechanism of the PCB-propylene interaction.     

The effects of adriamycin in vitro and in vivo on hepatic microsomal drug-metabolizing enzymes: role of microsomal lipid peroxidation

The quinone-containing anticancer drug adriamycin augments the reduction of dioxygen to reactive oxygen species and thereby stimulates (sixfold) NADPH-dependent microsomal lipid peroxidation. In vitro the extensive adriamycin-promoted peroxidation depleted (85%) rat liver microsomal cytochrome P-450, severely inhibited cytochrome P-450-dependent monooxygenation (70%), and glucose-6-phosphatase activity (80%), and activated (450%) UDP-glucuronyltransferase activity. When lipid peroxidation was blocked by EDTA, adriamycin selectively decreased cytochrome P-450 and aminopyrine N-demethylase activity; NADPH-cytochrome c reductase, UDP-glucuronyltransferase, and glucose-6-phosphatase activities were unchanged. Washing and resedimenting peroxidized microsomes to remove adriamycin and soluble lipid peroxidation products failed to restore enzyme activities to control values. Adriamycin administered subacutely (5 mg/kg × three doses) to rats significantly descreased hepatic microsomal cytochrome P-450 content and reduced aminopyrine N-demethylase and NADPH-cytochrome c reductase activities compared to saline-treated controls. Microsomal lipid peroxidation was increased following the above adriamycin treatment. Thus, these data suggested that adriamycin was capable of impairing hepatic drug metabolism in vitro by stimulating membrane lipid peroxidation in a manner similar to carbon tetrachloride; the mechanism by which adriamycin treatment in vivo decreased the activity of the drug monooxygenase system remains unclear.     

Depression of hepatic cytochrome P-450-dependent mixed function oxidases during infection with encephalomyocarditis virus

Infection of mice with encephalomyocarditis virus had a marked effect on drug biotransformation in the liver. the levels of cytochrome P-450 and cytochrome b₅ and aminopyrine N-demethylase activity were significantly decreased 3 days after the administration of lethal and sublethal doses of virus. Interferon was detected in serum at doses of virus that produced decreased drug biotransformation. Cytochrome P-450 content and aminopyrine N-demethylase activity remained at normal levels for the first 2 days following infection before reaching a maximum decrease on days 3 and 4. Concentration of interferon in the serum of infected mice appeared on day 2 of infection and reached peak levels on day 3. Increased heme oxygenase activity was associated with the decrease in cytochrome P-450 level during the infection. These studies indicate the existence of an interaction between virus infection and cytochrome P-450-dependent drug biotransformation. This may cause adverse toxic effects during the use of drugs that depend on the hepatic mixed function oxidases for elimination.     

Effect of racemic mephobarbital and d-mephobarbital on hepatic microsomal enzyme induction in rat and monkey

A standardized procedure for the routine measurement of hepatic mixed function oxidases including aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase, and azoreductase was used to examine enzyme alteration due to chronic drug administration. Oral treatment of monkeys or rats with either racemic mephobarbital or d-mephobarbital significantly increased liver weights and hepatic microsomal enzyme activities. Racemic mephobarbital-treated rats demonstrated higher hepatic enzyme activities compared to d-mephobarbital-treated rats. No differences were noted in the degree of induction of enzyme activities due to either isomer in the monkey.     

The effects of phenobarbitone on urinary 6β-hydroxycortisol excretion and hepatic enzyme activity in the marmoset monkey (callithrix jacchus)

The effect of phenobarbitone administration on hepatic drug metabolising activity and urinary 6β-hydroxycortisol excretion was investigated in the marmoset monkey (Callithrix jacchus). Phenobarbitone produced a significant increase in hepatic microsomal cytochrome P-450 content, aminopyrine N-demethylase activity, 7-ethoxycoumarin O-deethylase activity but no change in ethoxyresorufin O-deethylase activity. A significant increase in the urinary excretion of 6β-hydroxycortisol was observed after two days treatment with phenobarbitone.