Induction of hepatic cytochrome P-450 and xenobiotic metabolizing enzymes in rats gavaged with an Alberta crude oil

Changes in body weight gain and in biochemical parameters of blood and liver were assessed in Sprague-Dawley rats after multiple oral administration of three test doses of an Alberta crude oil (ACO). Rats treated with ACO (1.25-5 ml/kg) did not show statistically significant (p greater than .05) differences from control, corn-oil treated (5 ml/kg) rats, in body weight gains, liver weight, and blood biochemical indicators of liver (alanine aminotransferase, gamma glutamyltransferase), kidney (blood urea nitrogen, creatinine), and erythrocyte (adenosine 5'-triphosphate, 2,3-diphosphoglyceric acid, reduced glutathione) cytotoxicity. Treatment with ACO, however, caused statistically significant (p less than .05) and dose-related increases from control in (1) microsomal protein and cytochrome P-450 content, and NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase (AHH), and 7-ethoxycoumarin-O-deethylase (7-ECOD) activities, and (2) cytosolic glutathione transferase activity of liver. The induction of hepatic cytochrome P-450 and xenobiotic-metabolizing enzymes in microsomes of ACO-treated rats was probably associated with dose-related changes in isozymic forms of cytochrome P-450, as evidenced by (1) appearance of a 448-nm spectral peak in microsomes of ACO-treated rats and (2) differences in the inhibition pattern of AHH and 7-ECOD activities in microsomes of control and ACO-treated rats upon treatment with metyrapone and 7,8-benzoflavone.     

Influence of liver disease and environmental factors on hepatic monooxygenase activity in vitro

Summary The effects of liver disease and environmental factors on hepatic microsomal cytochrome P-450 content, NADPH-cytochrome c reductase (reductase) activity and aryl hydrocarbon hydroxylase (AHH) activity have been simultaneously investigated in 70 patients undergoing diagnostic liver biopsy. The activity of reductase was not significantly affected by the presence of liver disease or any of the environmental factors studied. Cytochrome P-450 content decreased with increasing severity of liver disease whereas AHH activity was only significantly reduced in biopsies showing hepatocellular destruction. None of the parameters of monooxygenase activity varied significantly with the age or sex of the patients. Alcohol excess was associated with decreased cytochrome P-450 content and AHH activity and this effect was independent of the histological status of the biopsy. Both high caffeine intake and cigarette smoking increased AHH activity in the absence of any change in cytochrome P-450 content. There was a positive correlation between the number of meat meals eaten per week and cytochrome P-450 content. Chronic treatment with enzyme-inducing anticonvulsants appeared to increase both cytochrome P-450 content and AHH activity. Despite differential effects of liver disease and environmental influences on cytochrome P-450 content and AHH activity there was a highly significant correlation between the two parameters. The results of the present study correlate well with the known effects of disease and environment on drug metabolism in vivo.     

Induction of rat-hepatic microsomal cytochrome P-450 and aryl hydrocarbon hydroxylase by 1,3-benzodioxole derivatives

Several 1,3-benzodioxoles (BD) and related compounds were studied in relation to their ability to generate metabolite complexes with hepatic cytochrome P-450 following administration in vivo to rats. BD derivatives that formed stable metabolite complexes with cytochrome P-450 were considerably more effective inducers of cytochrome P-450 and aryl hydrocarbon (benzo[alpha]pyrene) hydroxylase (AHH) activity than derivatives that did not form stable complexes. Linear regression analysis showed that AHH activity was well correlated (r = 0.980) with total (i.e. complexed plus uncomplexed) cytochrome P-450 content and was not correlated with levels of uncomplexed cytochrome P-450. Aminopyrine N-demethylase (APDM) activity in hepatic microsomes from rats treated with 1,3-benzodioxoles was moderately correlated in a linear relationship with uncomplexed levels of cytochrome P-450 and not with total cytochrome P-450.     

Induction of rat-hepatic microsomal cytochrome P-450 and aryl hydrocarbon hydroxylase by 1,3-benzodioxole derivatives

1. Several 1,3-benzodioxoles (BD) and related compounds were studied in relation to their ability to generate metabolite complexes with hepatic cytochrome P-450 following administration in vivo to rats.

2. BD derivatives that formed stable metabolite complexes with cytochrome P-450 were considerably more effective inducers of cytochrome P-450 and aryl hydrocarbon (benzo[α]pyrene) hydroxylase (AHH) activity than derivatives that did not form stable complexes.

3. Linear regression analysis showed that AHH activity was well correlated (r = 0.980) with total (i.e. complexed plus uncomplexed) cytochrome P-450 content and was not correlated with levels of uncomplexed cytochrome P-450.

4. Aminopyrine N-demethylase (APDM) activity in hepatic microsomes from rats treated with 1,3-benzodioxoles was moderately correlated in a linear relationship with uncomplexed levels of cytochrome P-450 and not with total cytochrome P-450.     

Characterization of hyperthyroidism enhancement of halothane-induced hepatotoxicity

Administration of anesthetic doses of halothane to hyperthyroid male rats results in the development of hepatic necrosis. The severity of the hepatic lesion was dependent on the dose of triiodothyronine (T3) and the length of time it was administered. Pretreatment of rats with iodinated metabolites of thyroxin which do not induce hyperthyroidism did not result in any signs of hepatotoxicity after halothane exposure. The administration of halothane to hyperthyroid female rats or mice of either sex did not result in the development of any overt hepatotoxicity. Likewise, hyperthyroidism did not enhance the hepatotoxicity of another hepatotoxin bromobenzene. The in vitro enzymatic activities associated with cytochrome P-450-dependent metabolism and glutathione S-transferase conjugation activity were markedly altered in hyperthyroid rats. Cytochrome P-450 levels, aminopyrine N-demethylase activity, glutathione levels and glutathione S-transferase activity were all significantly lower in hyperthyroid rats. However, other enzyme activities were stimulated by T3 pretreatment; aniline hydroxylase activity was increased by 45% and cytochrome c reductase activity was increased by 54% in hyperthyroid rats. Glutathione levels were also reduced significantly in hyperthyroid male rats. Maximal changes in both the cytochrome P-450 system and in the glutathione detoxification system were required before halothane demonstrated its hepatotoxic effects. Thus, a new balance between cytochrome P-450-dependent bioactivation and glutathione conjugation of halothane may be necessary for the exaggerated hepatotoxicity of halothane seen in hyperthyroid male rats.     

Lack of in vitro and in vitro effects of fenbendazole on phase I and phase II biotransformation enzymes in rats, mice and chickens.

Intraperitoneal administration of 10 mg fenbendazole/kg bw daily for 5 d caused no significant alterations in the activities of hepatic microsomal drug-metabolizing enzymes viz aminopyrine N-demethylase, aniline hydroxylase and cytosolic glutathione S-transferase in rats, mice and chickens. Similarly no significant difference in the amount of microsomal cytochrome P-450 and NADPH-cytochrome c reductase was found between control and treated animals. In vitro incubation of fenbendazole with rat, mouse and chicken microsomes suggests that the drug neither binds to microsomal protein cytochrome P-450 nor inhibits the activities of aminopyrine N-demethylase and aniline hydroxylase. Similarly in vitro addition of fenbendazole to cytosolic glutathione S-transferase from the above species did not alter the activity of this enzyme. The results indicate that fenbendazole does not alter the activity of hepatic microsomal monooxygenase system significantly in rats, mice and chickens at a dosage level of 10 mg/kg body weight. In vitro studies also indicate that fenbendazole does not interact with the hepatic microsomal monooxygenase system, indicating it is not a substrate for cytochrome P-450-dependent monooxygenase system.     

Monooxygenase activity of human liver in microsomal fractions of needle biopsy specimens.

1 Methods are described for the determination of mixed function oxidase activity in microsomal fractions from percutaneous needle biopsies of human liver. 2 Activities of needle biopsy samples were comparable with those of wedge biopsy sample obtained at laparotomy from different subjects. 3 Although cytochrome P-450 content of liver from rat and man was similar, human AHH activity was only 10% of that in the rat. 4 In biopsies with preserved hepatic architecture, AHH activity and cytochrome P-450 content showed a significant positive correlation. 5 Cigarette smoking significantly increased both AHH activity and turnover number, but not cytochrome P-450 content, of biopsies with normal architecture. 6 The presence of liver disease caused a significant decrease in AHH activity and cytochrome P-450 content.     

一种新的多环芳烃型药物代谢酶诱导剂—抗早孕药DL-111-IT

以抗早孕药3-(2-乙基苯基)-5-(3-甲氧基苯基)-1-氢-1,2,4-三唑(DL-111-IT)80 mg/kg预处理大鼠4 d,大鼠肝重无显著增加,但肝微粒体P-450含量为对照组值1.5倍左右、P-450一氧化碳络合物吸收峰波长短移、AHH催化活性显著增高、UDPGT缀合平面型底物的能力提高至2倍左右,而肝微粒体P-450与甲吡酮及对氨基苯甲酸叔丁酯代谢中间体络合的能力不变或下降,表明DL-111-1T或许是一种新的多环芳烃型药物代谢酶诱导剂。     

Drug Metabolism Activities of Isolated Rat Hepatocytes in Monolayer Culture

Abstract: The levels of cytochrome P-450 in hepatocytes cultured as monolayers for 22 hrs in Dulbecco's modified Eagle medium supplemented with serum and insulin was reduced to approximately 40% of initial values of freshly isolated hepatocytes. In correspondance with this the activities of the cytochrome P-450 monooxygenases aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) and ethylmorphine (EM) N-demethylase were reduced to 40 and 22% of their initial activities, respectively. Modifying the culture medium through omission of cysteine and cystine, and adding dexamethazone and delta-amino levulinic acid, increased the content of cytochrome P-450 to 59 % and EM N-demethylase to 46 % of initial values, but was without effect on AHH activity. However, further modifications by adding high concentrations of asparagine and leucine increased AHH activity to 62% of initial values, but did not further enhance the total content of cytochrome P-450 or the EM N-demethylase activity. The activities of cytochrome P-450 reductase, flavin containing monooxygenase, epoxide hydrolase and glutathione S-transferase decreased less (to about 70–80% of initial values) than cytochrome P-450 associated monooxygenase activities, whereas UDP-glucuronyl transferase decreased to about 50% of initial values. In contrast to what was observed regarding cytochrome P-450 and associated monooxygenase activities, modification of the incubation conditions did not affect the non-cytochrome P-450 enzymatic activities.     

一种新的多环芳烃型药物代谢酶诱导剂—抗早孕药DL-111-IT

以抗早孕药3-(2-乙基苯基)-5-(3-甲氧基苯基)-1-氢-1,2,4-三唑(DL-111-IT)80 mg/kg预处理大鼠4 d,大鼠肝重无显著增加,但肝微粒体P-450含量为对照组值1.5倍左右、P-450一氧化碳络合物吸收峰波长短移、AHH催化活性显著增高、UDPGT缀合平面型底物的能力提高至2倍左右,而肝微粒体P-450与甲吡酮及对氨基苯甲酸叔丁酯代谢中间体络合的能力不变或下降,表明DL-111-1T或许是一种新的多环芳烃型药物代谢酶诱导剂。     

Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxan-induced diabetic rats

Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosamines (NNA) are mainly activated by cytochrome P450s, and their associated enzyme activities such as aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH), N-nitrosdimethylamine N-demethylase I (NDMA-dI), NADPH-cytochrome C reductase, and detoxified by glutathione S-transferase (GST) and glutathione (GSH). The present study shows the influence of Cymbopogon proximus (Halfa barr), Zygophyllum coccineum L. (Kammun quaramany), Lupinus albus (Termis) as herbs capable of inducing hypoglycemia on the activity of the above mentioned enzymes in the liver of diabetic rats. Alloxan was administered as a single dose (120 mg/kg body weight) to induce diabetes and the herbs were administered to diabetic rats as repeated doses for 4 weeks. Alloxan-induced diabetes significantly increased the blood glucose level by 93% compared to the control level. On the other hand, repeated-dose treatments of diabetic rats with Cymbopogon proximus and Lupinus albus are more effective than Zygophyllum coccineum in restoring the elevated blood glucose level to the normal level. Alloxan treatment increased the hepatic activity of cytochrome P450, NADPH-cytochrome C reductase, AHH, NDMA-dI, GST and GSH by 112, 122, 82, 99, 64 and 26%, respectively. These herbs decreased the activity of above mentioned enzymes in the liver of diabetic rats compared to alloxan-treated rats. We conclude that alloxan increased the activity of cytochrome P450 system and that such herbs reduced these activities. The toxic effects of PAHs (e.g. benzo(a)pyrene) and NNA (e.g. N-nitrosdimethylamine) could be increased in the liver of diabetic rats through induction of their corresponding bioactivating enzymes. On the other hand, hypoglycemic herbs could alleviate the deleterious effects of these carcinogens in the liver of diabetic rats since these herbs reduced the hepatic content of cytochrome P450 and other associated enzyme activities compared to the diabetic group. Such alterations in the activity of phase I and II drug-metabolizing enzymes should be considered when therapeutic drugs are administered to diabetic patients since most of drugs are metabolized mainly by the cytochrome P450 system.     

Age-dependent toxicity of acorn extract in young and old male rats

Intraperitoneal administration of acorn extract of dosage levels of 200, 400 and 600 mg/kg body weight did not produce significant change in the hepatic microsomal cytochrome P-450 levels and the activities of NADPH-cytochrome c reductase, benzphetamine N-demethylase and aniline hydroxylase in young, adult rats (weighing 200-250 g), with the exception of the activity of benzphetamine N-demethylase at the 600 mg/kg dose which was decreased significantly. On the other hand, a dose of only 100 mg/kg body weight ip to old rats (weighing 400-450 g) caused significant decreases in the microsomal cytochrome P-450, benzphetamine N-demethylase and NADPH-cytochrome c reductase activities. However, there was no significant change in the activity of aniline hydroxylase in these rats, indicating selective inhibition of the microsomal enzymes and higher susceptibility of old rats than young ones to acorn toxicants. When the serum samples from the treated young rats were analyzed for sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as markers of liver toxicity, these activities were significantly higher in the treated rats than the corresponding control values. Similar changes were noted for old rats receiving a dose of 100 mg/kg body weight of acorn extract. The results indicate that acorn extract affects old rats more than young rats as measured by its effect on liver and liver microsomal enzymes.     

Interaction of endosulfan and dietary vitamin A on rat hepatic drug metabolising enzymes

The effect of interaction of Endosulfan, a chlorinated insecticide of the cyclodiene group, with dietary vitamin A on the hepatic mixed function oxidase system in rats has been studied. Endosulfan administration (ten days) significantly increased microsomal protein content and cytochrome P-450 levels, NADPH cytochrome C-reductase aminopyrine N-demethylase and aniline hydroxylase activities, with respect to control rats. Administration of vitamin A (10,000 I.U./100 g body weight) daily for ten days reduced the activity of the above mentioned enzymes, when vitamin A and endosulfan were given together, vitamin A reduced the endosulfan induced increase of microsomal proteins and cytochrome P-450 levels, the activity of NADPH cytochrome C-reductase, aminopyrine N-demethylase and aniline-hydroxylase.     

Effects of dimethylformamide on hepatic microsomal monooxygenase system and glutathione metabolism in rats.

The effects of repeated exposure to N,N-dimethylformamide (DMF) on hepatic microsomal monooxygenase system and glutathione metabolism were investigated. DMF was administered to Wistar male rats by subcutaneous (s.c.) injection at 0.5 ml/kg body weight daily for 1 week. Macroscopically, mild liver swelling was observed and liver weights significantly increased after 1 week of exposure to DMF. Hematological changes were not detected. In exposed rats, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, cholinesterase and total cholesterol significantly increased. Hepatic microsomal cytochrome P-450 and protoheme decreased by 34% and 24%, respectively, while microsomal protein and cytochrome b5 were not affected. NADH-ferricyanide reductase activity decreased by 24% while NADPH-cytochrome c reductase activity showed no change. Glutathione reductase (GR) activity showed a significant decrease after the first injection and remained depressed throughout the study, with no change in glutathione peroxidase (GPx) activity. Glutathione S-transferase (GST) activity showed a significant increase at 3 days after DMF treatment and gradually increased by 66% at 1 week. In a subsequent experiment with a single administration of DMF (4 ml/kg), reduced glutathione (GSH) in the liver was decreased by 28% at 8 h, but recovered to control levels by 24 h. These results indicate that DMF alters the hepatic microsomal monooxygenase system and glutathione metabolism. These findings may greatly contribute to the elucidation of the pathogenesis of DMF hepatotoxicity.     

Induction of pulmonary and hepatic cytochrome P-450 species by coal fly ash inhalation in rats

The effect of fly ash inhalation on xenobiotic metabolizing enzymes and heme metabolism in lung and liver has been studied in rats. Fly ash inhalation induced pulmonary and hepatic cytochrome P-450 content, aryl hydrocarbon hydroxylase and glutathione S-transferase activity. Induction of cytochrome P-450 was accompanied by induction of delta-amino levulinic acid synthetase in lung and inhibition of heme oxygenase in both lung and liver. Fly ash inhalation induced those species of cytochrome P-450 which closely resembled cytochrome P-448 in spectral properties and electrophoretic mobility.     

EFFECTS OF MOTORCYCLE EXHAUST ON CYTOCHROME P-450-DEPENDENT MONOOXYGENASES AND GLUTATHIONE S-TRANSFERASE IN RAT TISSUES

The effects of motorcycle exhaust (ME) on cytochrome P-450 (P-450) -dependent monooxygenases were determined using rats exposed to the exhaust by either inhalation, intratracheal, or intraperitoneal administration. A 4-wk ME inhalation significantly increased benzo[a]pyrene hydroxylation, 7-ethoxyresorufin O-deethylation, and NADPH-cytochrome c reductase activities in liver, kidney, and lung microsomes. Intratracheal instillation of organic extracts of ME particulate (MEP) caused a dose- and time-dependent significant increase of monooxygenase activity. Intratracheal treatment with 0.1 g MEP extract/ kg markedly elevated benzo[a]pyrene hydroxylation and 7- ethoxyresorufin O-deethylation activities in the rat tissues 24 h following treatment. Intraperitoneal treatment with 0.5 g MEP extract/ kg/d for 4d resulted in significant increases of P-450 and cytochrome b contents and NADPH-cytochrome c reductase 5 activity in liver microsomes. The intraperitoneal treatment also markedly increased monooxygenases activities toward methoxyresorufin, aniline, benzphetamine, and erythromycin in liver and benzo[a]pyrene and 7-ethoxyresorufin in liver, kidney, and lung. Immunoblotting analyses of microsomal proteins using a mouse monoclonal antibody (Mab) 1-12-3 against rat P-450 1A1 revealed that ME inhalation, MEP intratracheal, or MEP intraperitoneal treatment increased a P-450 1A protein in the hepatic and extrahepatic tissues. Protein blots analyzed using antibodies to P-450 enzymes showed that MEP intraperitoneal treatment caused increases of P-450 2B, 2E, and 3A subfamily proteins in the liver. The ME inhalation, MEP intratracheal, or MEP intraperitoneal treatment resulted in significant increases in glutathione S -transferase activity in liver cytosols. The present study shows that ME and MEP extract contain substances that can induce multiple forms of P-450 and glutathione S-transferase activity in the rat.     

Differential induction of cytochrome P-450 catalyzed activities by polychlorinated biphenyls and benzo [a]pyrene in B6C3F1 mouse liver and lung

The properties of some constitutive and inducible enzyme activities of liver and lung microsomes were determined in B6C3F1 mice pretreated by either intratracheal (i.t.) administration of benzo[a]pyrene (BaP) or polychlorinated biphenyl (PCBs) mixture (Aroclor 1254), or intraperitoneal (i.p.) administration with Aroclor 1254. After i.p. administration of Aroclor 1254, liver cytochrome P-450 content, aryl hydrocarbon hydroxylase (AHH), benzphetamine N-demethylase and nitroreductase activities were increased 2.8-, 2.0-, 2.2-, and 2.0-fold, respectively. Lung cytochrome P-450 content was also increased (1.9-fold) after i.p. administration of Aroclor 1254; AHH and nitroreductase activities, however, were not affected and benzphetamine N-demethylase activity was decreased. Aroclor 1254 administered i.t. did not affect liver cytochrome P-450 content. However, AHH and benzphetamine N-demethylase activities were decreased 1.4- and 1.2-fold, respectively, and nitroreductase activity was increased 1.6-fold. After i.t. administration of Aroclor 1254, lung cytochrome P-450 content and AHH activity were increased 1.4- and 2.2-fold, respectively. Benzphetamine N-demethylase activity was decreased 2.1-fold and nitroreductase activity was not affected. After i.t. administration of BaP, liver 7-ethoxyresorufin O-deethylase and nitroreductase activities were increased 2.2- and 1.5-fold, respectively, and benzphetamine N-demethylase activity was decreased 1.3-fold. Lung AHH and 7-ethoxyresorufin O-deethylase activities were increased 4.3- and 3.1-fold, respectively, and cytochrome P-450 content, benzphetamine N-demethylase and nitroreductase activities were decreased 1.4-, 1.2- and 1.3-fold, respectively, after BaP administration. These data indicate that different cytochrome P-450 isozymes induced in B6C3F1 mice are responsible for monooxygenase and nitroreductase activities, and that the route of administration of chemicals is important in the expression of cytochrome P-450 catalyzed activities.     

Biochemical toxicology of argemone oil. I. Effect on hepatic cytochrome P-450 and xenobiotic metabolizing enzymes

The in vivo effect of argemone oil on hepatic xenobiotic metabolizing enzymes was investigated in albino rats following either a single (10 ml kg-1 body wt.) or multiple intraparenteral doses (5 ml kg-1 body wt.) for three days. Animals sacrificed 72 h after a single intraparenteral dose of argemone oil exhibited a significant loss of hepatic cytochrome P-450 (35%) and cytochrome b5 (34%) contents and inhibition of aminopyrine-N-demethylase (APD), aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin-O-deethylase (ECD) activities (21-39%). Three successive 24-hourly intraparenteral injections of argemone oil followed by sacrificing the animals after 24 h of the last injection, showed a greater degree of inhibition of the content of cytochrome P-450 (58%) and its dependent mixed-function oxidases (35-63%). Also, multiple treatment of argemone oil caused a depletion of endogenous hepatic glutathione (GSH) content (72%) with a concomitant increase in lipid peroxidation (177%) and decrease in glutathione-S-transferase (GST) activity (30%). A significant decrease in relative liver weight (39%) was observed in animals treated with multiple treatment of argemone oil. These results suggest that argemone oil can alter both membrane and cytosolic defences and destabilizes the hepatic cytochrome P-450 dependent mixed-function oxidase system, so that it tips in the direction of autooxidative peroxidation of lipids.     

The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies.

Four cytochrome P-450 enzyme activities, 7-ethoxyresorufin O-deethylase (ERDE), coumarin 7-hydroxylase (CH), 7-ethoxycoumarin O-deethylase (ECDE) and aryl hydrocarbon hydroxylase (AHH) were measured in human liver needle biopsy samples from smokers and non-smokers. Cigarette smoking was verified and quantitated by measuring plasma cotinine levels. Enzyme inhibitory monoclonal antibodies (MAb) to a 3-methylcholanthrene-induced (MAb 1-7-1) and phenobarbitone-induced (MAb 2-66-3) rat hepatic cytochrome P-450 were used to measure the contribution of MAb-defined, epitope-specific cytochromes P-450 to the total reaction measured for each of the above activities. ERDE activity was significantly elevated in the livers of cigarette smokers, whereas AHH, CH or ECDE activities were not affected by cigarette smoking. No correlation was observed between plasma cotinine concentration and ERDE activity. MAb 1-7-1 inhibited hepatic ERDE activity to a variable extent (from 0 to 65%), but had very little or no effect on AHH, CH or ECDE activities. The inhibitory effect of MAb 1-7-1 on ERDE activity was greater than 50% in the non-smokers. MAb 2-66-3 had no inhibitory effect on any of the enzyme activities studied. In contrast to liver both ERDE and AHH on human placental microsomes from cigarette smokers were inhibited by MAb 1-7-1. The MAb 2-66-3 was without effect. Cigarette smoking induces a form of P-450 in human liver, responsible for ERDE activity, that contains an epitope recognized by MAb 1-7-1. This form of cytochrome P-450 is insensitive to MAb 2-66-3 and is not contributing to AHH, CH or ECDE activities of human liver.     

Effect of monensin on liver glutathione, glutathione S-transferase and monooxygenases in rats.

Monensin administered ip to male rats at a dosage of 2.5 mg/kg/d for 3 consecutive days did not change the liver levels of glutathione, but depressed significantly the amount of cytochrome P-450 and the activities of aniline hydroxylase and a cytosolic CDNB-specific glutathione S-transferase. There was a marked decrease in the aminopyrine N-demethylase activity and a significant increase in the pentobarbital sleeping time in rats treated with monensin. In contrast, no change in these parameters was found 2 h after a single ip dose (7.5 mg/kg) of monensin. The results suggest that monensin-induced inhibition of the liver cytosolic glutathione S-transferase and microsomal monooxygenases is non-specific.