Hepatic Microsomal Drug-metabolizing Enzymes Research Articles

Pharmacokinetic and Pharmacodynamic Interactions of Ethanol and Propofol in Rabbits

Propofol is a short-acting intravenous anesthetic which is rapidly metabolized by glucuronidation and ring hydroxylation catalyzed by cytochrome P450. In clinical trials, it was found that patients receiving both ethanol and propofol injection in the surgery awoke significantly earlier than those who were injected propofol alone. To investigate pharmacokinetic and pharmacodynamic interactions of propofol and ethanol, propofol was injected alone and in combination with ethanol to rabbits. Propofol was injected intravenously at a dose rate of 15 mg kg−1. Ethanol was injected intraperitoneally at a dose rate of 2.5 mg kg−1. An LC assay with native fluorescence detection was developed and validated for determining the concentration of propofol in rabbit plasma and the effect of co-injected ethanol on the plasma pharmacokinetics of propofol in rabbits. Co-injection of ethanol decreased the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC0–∞) of propofol by 53.28 and 53.42%, respectively, as compared to the control (P < 0.001). Concomitant ethanol also caused a 66.67% increase in plasma clearance (CL) (P < 0.001). These may partially explain the finding that co-injected ethanol reduced the anesthetic effect of propofol by introducing hepatic microsomal drug-metabolizing enzymes activity in rabbits.

Nuclear Receptor Ligands: Rational and Effective Therapy for Chronic Cholestatic Liver Disease?

p r f c t p p f c he regulation of genes that are essential to many hepatic metabolic and transport functions are medited in large part by the action of small molecules that unction as nuclear receptor ligands.1 This process has een labeled chemical genomics.2 These ligands bind to heir specific nuclear receptors, activating the receptor hat then binds to specific elements in a gene’s promoter esulting in stimulation or inhibition of gene expresion.3 In the liver many drugs, metabolites, and herbal ompounds exert their biologic properties as ligands for uclear receptors.4,5 Some familiar examples of drugs hat activate nuclear receptors include phenobarbital and t John’s wort. Both drugs induce hepatic drug metablizing enzymes by acting as ligands for the pregnane X eceptor (PXR), which binds to specific response eleents in the promoter of cytochrome P-450 3A CYP3A), a major hepatic microsomal drug–metabolizng enzyme. This induction then indirectly affects the etabolism and systemic effects of a wide variety of other ompounds metabolized by CYP3A. An extract of 4 ifferent plants, Yin Zhi Huang, has been used tradiionally for treating neonatal jaundice in China and is a igand for the constitutive androstane receptor (CAR) hat up-regulates the expression of several different liver ransporters and enzymes involved in the hepatic clearnce of serum bilirubin.5 Indeed, more than 10% of edically useful drugs are known to exert their biologic ehavior by binding to ligand-binding domains on speific nuclear receptors.4 Table 1 shows some of the most mportant nuclear receptors and their physiologic ligands hat determine the hepatic transport and metabolism of variety of xenobiotics and endogenous substrates. In this issue of GASTROENTEROLOGY, Marschall et al6 eport that rifampicin and ursodeoxycholic acid (UDCA), wo well-known drugs used in the treatment of cholesatic liver disease, each stimulate the transcription of a istinct set of genes that together decrease bile acid ptake, enhance bile acid detoxification and excretion, nd stimulate the clearance of bilirubin. Rifampicin inreased the expression of CYP3A4, uridine 5=-glucuonosyl transferase (UGT1A1), and multidrug-resisance–associated protein (MRP2) whereas UDCA timulated the bile salt export pump (BSEP), and mulidrug resistance protein (MDR3), and MRP4. Although hese effects were observed in patients undergoing choecystectomy who otherwise were healthy, these separate ut complementary effects on gene and protein expresion are predicted to have beneficial effects if they ocurred in patients with cholestatic liver disease. These ndings thus suggest that there is therapeutic benefit rom combining drugs such as rifampicin and UDCA hat target nuclear receptors that have coordinated effects n the transcriptional regulation of hepatobiliary excreory mechanisms.7 How does this occur? The hepatic clearance of bile acids and bilirubin can be ivided into 4 phases that include the following: phase 0, epatic uptake; phase I, metabolism (eg, hydroxylation); hase II, detoxification (eg, conjugation); and phase III, xcretion. Nuclear receptors and their ligands that are he major determinants of the functional expression of enes that determine these pathways are shown in Figure , together with enzymes that control bile acid synthesis. In the enterohepatic circulation, the hepatic uptake of onjugated bile acids (phase 0) is mediated predominantly y the sodium taurocholate cotransporting polypeptide TCP (SLC10A1), whereas unconjugated bile acid uptake s facilitated by several organic anion transporting polypepides (OATPs) on the sinusoidal membrane, but predomi-

Effects of long-term tea polyphenols consumption on hepatic microsomal drug-metabolizing enzymes and liver function in Wistar rats.

To investigate the effects of long-term tea polyphenols (TPs) consumption on hepatic microsomal drug-metabolizing enzymes and liver function in rats. TPs were administered intragastrically to rats at the doses of 833 mg.kg(-1).d(-1) (n=20) and 83.3 mg.kg(-1).d(-1) (n=20) respectively for six months. Controlled group (n=20) was given same volume of saline solution. Then the contents of cytochrome P450, b5, enzyme activities of aminopyrine N-demethylase (ADM), glutathione S-transferase (GST) and the biochemical liver function of serum were determined. The contents of cytochrome P450 and b5 in the livers of male rats in high dose groups (respectively 2.66 +/- 0.55, 10.43 +/- 2.78 nmol.mg MS pro(-1)) were significantly increased compared with the control group (1.08 +/- 1.04, 5.51 +/- 2.98 nmol.mg MS pro(-1); P<0.01, respectively). The enzymatic activities of ADM in the livers of female rats in high dose groups (0.91 +/- 0.08 mmol.mg MS pro(-1)min(-1)) were increased compared with the control group (0.82 +/- 0.08 mmol.mg MS pro(-1).min(-1); P<0.05). The GST activity was unchanged in all treated groups, and the function of liver was not obviously changed. The antidotal capability of rats' livers can be significantly improved after long-term consumption of TPs. There are differences in changes of drug-metabolizing enzymes between the sexes induced by TPs and normal condition.

Induction of hepatic microsomal drug-metabolizing enzymes by inhibitors of 5-lipoxygenase (5-LO): studies in rats and 5-LO knockout mice.

The effect of 5-lipoxygenase (5-LO) inhibitors on the hepatic microsomal mixed-function oxidase (MFO) system of rodents was investigated. After establishing the relative in vitro and in vivo potencies of the 3 test compounds, male Crl:CD (SD) BR rats received CJ-11,802 (0, 10, 50, or 200 mg/kg/day), zileuton (0, 10, 60, or 300 mg/kg/day) or ZD2138 (0 or 200 mg/kg/day) once daily by oral gavage for 14 (zileuton and ZD2138) or 30 (CJ-11,802) consecutive days. Controls were given an equivalent volume of 0.5% methylcellulose vehicle. At necropsy, all livers were weighed, and sections from representative animals (control and highest dose for each compound) were utilized to prepare hepatic microsomal fractions, which were assayed for cytochrome P-450 (CYP) content and the activities of cytochrome c reductase (CRed), para-nitroanisole O-demethylase (p-NOD), ethoxyresorufin O-deethylase (EROD), and pentoxyresorufin O-dealkylase (PROD). A dose-related increase in liver weight occurred in rats given CJ-11,802 and zileuton, while animals administered ZD2138 were unaffected. Rats given CJ-11,802 (200 mg/kg/day) and zileuton (300 mg/kg/day) had increases in CYP, EROD, PROD, CRed and p-NOD compared to corresponding controls, while only the latter two activities were elevated in animals administered ZD2138. To determine if induction of the hepatic microsomal MFO system was related to 5-LO inhibition, male DBA wild-type and 5-LO knockout mice were administered either CJ-11,802 (200 mg/kg/day) or vehicle by oral gavage for 14 consecutive days. At necropsy, liver weight, CYP content, and CRed activity were measured and all were increased similarly in the treated wild-type and knockout mice compared to corresponding controls, indicating that induction was not related to inhibiting 5-LO.

The role of 3-methylsulfonyl-2,2′,4′,5,5′-pentachlorobiphenyl, a metabolite of 2,2′,4,5,5′-pentachlorobiphenyl, in the induction of hepatic microsomal drug-metabolizing enzymes by 2,2′,4,5,5′-pentachlorobiphenyl in rats

After the administration of 2,2′,4,5,5′-pentachlorobiphenyl (2,2′,4,5,5′-pentaCB) to intact rats, the concentration of 2,2′,4,5,5′-pentaCB in liver gradually decreased, whereas 3-methylsulfonyl (3-MeSO 2)-2,2′,4′,5,5′-pentaCB appeared in liver and remained detectable in liver for 6 weeks. A single injection of 2,2′,4,5,5′-pentaCB (342 μmol/kg) or 3-MeSO 2-2,2′,4′,5,5′-pentaCB (0.5 μmol/kg) caused a significant increase both in the contents of cytochromes P450 and b 5 and in the activities of aminopyrine N-demethylase and benzo[ a]pyrene hydroxylase, and the increased enzyme contents and activities continued for 6 weeks after the administration. The extent of both the hepatic accumulation of 3-MeSO 2-2,2′,4′,5,5′-pentaCB and the induction of the enzymes for 6 weeks after the administration of 2,2′,4,5,5′-pentaCB was similar to that after the administration of 3-MeSO 2-2,2′,4′,5,5′-pentaCB. 3-MeSO 2-2,2′,4′,5,5′-pentaCB was considered to play a principal role in the induction of microsomal drug-metabolizing enzymes by 2,2′,4,5,5′-pentaCB. When 2,2′,4,5,5′-pentaCB was injected i.p. into bile duct-cannulated rats, 3- and 4-MeSO 2-2,2′,4′,5,5′-pentaCBs were not detected in liver. In antibiotic-treated rats dosed with 2,2′,4,5,5′-pentaCB, the concentrations of 3- and 4-MeSO 2-2,2′,4′,5,5′-pentaCBs in liver were markedly reduced. These findings suggest that the process in which 3- and 4-MeSO 2 metabolites of 2,2′,4,5,5′-pentaCB are formed involves the biliary secretion of some precursors which will be subjected to metabolism by intestinal microflora. The increasing effects of 2,2′,4,5,5′-pentaCB both on the content of cytochrome P450 and on the activity of aminopyrine metabolizing enzyme in hepatic microsomes were not observed in the bile duct-cannulated rats, in which the phenobarbital treatment enabled the drug-metabolizing enzymes to be induced. In antibiotic-treated rats, the increases both in the cytochrome P450 content and in the aminopyrine N-demethylase activity after the administration of 2,2′,4,5,5′-pentaCB were smaller than those observed in the intact rats. These findings provide the evidence that the induction of some drug-metabolizing enzymes by 2,2′,4,5,5′-pentaCB is due not to the action of 2,2′,4,5,5′-pentaCB itself but to its 3-methylsulfonyl metabolite, 3-MeSO 2-2,2′,4′,5,5′-pentaCB.

Exposure of hemodialysis patients to di-2-ethylhexyl phthalate

The migration of di-2-ethylhexyl phthalate (DEHP) from dialyzers was studied in 21 patients with chronic renal failure undergoing maintenance hemodialysis. The circulating concentrations of DEHP were measured by high performance liquid chromatography in blood of patients obtained from the inlet and the outlet of the dialyzer during a 4-h dialysis session. During treatment of renal failure using plasticized tubing, the plasma level of DEHP increased. On average, an estimated 75.2 mg of DEHP was extracted from the dialyzer during a single dialysis session, with a range of 44.3–197.1 mg. On the other hand, the total amount of DEHP retained by the patient during the dialysis session was evaluated by the difference between the AUC out and the AUC in and ranged from 3.6 to 59.6 mg. The rate of extraction of DEHP from the dialyzer was correlated ( r=0.705, P<0.05) with serum lipid content (cholesterol and triglyceride). So, we confirmed that patients on hemodialysis are always regularly exposed to considerable amounts of DEHP. However, several metabolic effects have been reported in various animal species following treatment with DEHP, such as changes in lipid metabolism and in hepatic microsomal drug-metabolizing enzyme activities. DEHP is now a well-known hepatic peroxisomal proliferator in rodents and an inducer of many peroxisomal and non-peroxisomal enzymes. So, lipid metabolism modifications and hepatic changes observed in hemodialysis patients could be explained from chronic exposition to DEHP. In the coming years, it seems necessary to reconsider the use of DEHP as a plasticizer in medical devices. Highly unacceptable amounts of DEHP leached during the dialysis session could be easily avoided by careful selection of hemodialysis tubing.

Mechanism of Inhibitory Effects of Cannabidiol and Cannabidiol Hydroxy-quinone on the Hepatic Microsomal Drug-Metabolizing Enzymes in Mice (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Mechanism of Inhibitory Effects of Cannabidiol and Cannabidiol Hydroxy-quinone on the Hepatic Microsomal Drug-Metabolizing Enzymes in Mice (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Evidence That 3-Methylsulfonyl Metabolite of 2, 2', 4, 5, 5'-Pentachlorobiphenyl Is Causative Substance of Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by the Parent Compound in Rats (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Evidence That 3-Methylsulfonyl Metabolite of 2, 2', 4, 5, 5'-Pentachlorobiphenyl Is Causative Substance of Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by the Parent Compound in Rats (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by 3-Methylsulfonyl-2, 2', 4', 5, 5'-Pentachlorobiphenyl in Female Rats (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by 3-Methylsulfonyl-2, 2', 4', 5, 5'-Pentachlorobiphenyl in Female Rats (Proceedings of the 23rd Symposium on Toxicology and Environmental Health)

Comparison of effects of xenobiotics on extrahepatic and hepatic microsomal drug-metabolizing enzymes in mice

The content of microsomal protein is the same in both kidneys and small intestine, corresponding to 57% of the control value expressed as 100% in the untreated liver. The contents of P450 and cytochrome b 5, and the activity of NADPH-cytochrome c reductase in the kidney were higher than those in the small intestine, which were 17%, 22% and 41% of controls, respectively, in the former and 5%, 11% and 22% of controls in the latter. As compared with similar measurements made in the liver, the activities of substrate-metabolizing enzymes in these extrahepatic organs were very low. The activities of renal aniline hydroxylase, aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase, 7-methoxycoumarin O-demethylase and benzo(a)pyrene hydroxylase were 6%, 5%, 3%, 0.6% and 0.2% of controls, respectively. The activities of these enzymes in the small intestine were lower than those in the kidney or below the limits of detection. These results suggested that isoforms or their contents of P450 responsible for these substrate biotransformations are different among liver, kidneys and small intestine. Meantime, this study showed similar significant inductions by phenobarbital and rifampin of small intestinal and hepatic microsomal drug-metabolizing enzymes. In contrast, neither phenobarbital nor rifampin was capable of increasing renal microsomal enzymes, with the exception of benzo(a)pyrene hydroxylase which was induced by rifampin. These findings indicated that both liver and small intestine, but not kidneys contain the same phenobarbital- and rifampin-inducible P450 isoforms, cytochrome b 5 and NADPH-cytochrome c reductase. In addition, CCl 4 could be bioactivated by CYP2E1 to free radicals in the kidney which caused destruction of microsomal enzymes. In mice pretreated with phenobarbital, CCl 4 also attenuated the increase in content of P450 in the small intestine, which appeared to be a result of induction by phenobarbital of CYP2E1.

Effect of fluvastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl CoA reductase, on drug-metabolizing enzymes in rats

Fluvastatin (FV), a new cholesterol-lowering agent, has been studied for its effects on hepatic microsomal drug-metabolizing enzymes in male rats. FV was orally administered in dosages of 1, 5, and 30 mg/kg/day for 7 consecutive days. 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activities were markedly decreased at all dose levels. The amount of microsomal protein and the contents of cytochromes P450 and b5 did not change. No induction of aniline hydroxylase, aminopyrine N-demethylase, testosterone hydroxylases (15 alpha-, 7 alpha-, 6 beta-, 16 alpha-, and 16 beta-), and UDP-glucuronosyltransferase were found. On the other hand, 7-ethoxycoumarin o-deethylase activity was slightly increased and lauric acid omega-1-hydroxylase activity tended to be decreased after treatment with FV.

Induction of hepatic microsomal drug-metabolizing enzymes by methylsulphonyl metabolites of polychlorinated biphenyl congeners in rats

The effect of methylsulphonyl (MeSO 2) metabolites of 2,3′,4′,5-tetrachlorobiphenyl (tetraCB) (IU-70), 2,2′,3′,4′,5-pentachlorobiphenyl (pentaCB) (IU-87), 2,2′,4′,5,5′ -pentaCB (IU-101) and 2,2′,3′,4′,5,5′-hexachlorobiphenyl (hexaCB) (IU-141), on the hepatic microsomal drug-metabolizing enzyme system was investigated in rats. The administration of 3-MeSO 2-2,3′,4′,5-tetraCB (10 μmol/kg), 3-MeSO 2-2,2′,3′,4′,5-pentaCB (0.5 μmol/kg), 3-MeSO 2-2,2′,4′,5,5′-pentaCB (0.5 μmol/kg) and 3-MeSO 2-2,2′,3′,4′,5,5′-hexaCB (2 μmol/kg) to rats significantly increased the contents of cytochromes P-450 and b 5 and the activities of aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and benzo[ a]pyrene hydroxylase. From these results, it is suggested that the 3-MeSO 2 derivatives studied are possibly potent phenobarbital-like inducers of microsomal drug-metabolizing enzymes. On the other hand, 4-MeSO 2-2,3′,4′,5-tetraCB, 4-MeSO 2-2,2′,3′,4′,5-pentaCB, 4-MeSO 2-2,2′, 4′,5,5′-pentaCB and 4-MeSO 2-2,2′,3′,4′,5,5′-hexaCB had almost no effect on both cytochrome contents and these enzyme activities. After 96 h, following administration of 2,3′,4′,5-tetraCB, 2,2′,3′,4′,5-pentaCB, 2,2′,4′,5,5′-pentaCB and 2,2′,3′,4′,5,5′-hexaCB

Enhanced teratogenic activity of di- n-butyltin diacetate by carbon tetrachloride pretreatment in rats

Di- n-butyltin diacetate (DBTA) has been shown previously to cause malformations such as cleft mandible, ankyloglossia and fused ribs in rat foetuses after oral treatment of dams on day 8 of gestation. In this study, effects of pretreatment with carbon tetrachloride (CCl 4) on the teratogenic activity of DBTA were examined in Wistar rats. Pregnant rats were pretreated sc with CCl 4 (0.5 ml/kg) on days 6 and 7 of gestation and were treated orally with DBTA on day 8 of gestation at doses of 0, 4.5, 10 or 22 mg/kg. Caesarean sections were performed on day 20 of gestation, and foetuses were examined for external and skeletal anomalies. Pretreatment with CCl 4 enhanced the incidence of external and skeletal malformations caused by DBTA. Concentrations of di- n-butyltin in embryos, maternal liver and maternal blood on day 9 of gestation were increased by CCl 4 pretreatment, which inhibited the activity of maternal hepatic microsomal drug-metabolizing enzymes. These results suggest that there is little probability that metabolites of DBTA make a critical contribution to the teratogenicity of DBTA.

Effects of Methylsulfonyl Metabolites of PCBs Accumulated in Tissues of Mammals on Activities of Hepatic Microsomal Drug-Metabolizing Enzymes in Rats (Proceedings of the 19th Symposium on Toxicology and Environmental Health)

Effects of Methylsulfonyl Metabolites of PCBs Accumulated in Tissues of Mammals on Activities of Hepatic Microsomal Drug-Metabolizing Enzymes in Rats (Proceedings of the 19th Symposium on Toxicology and Environmental Health)

Role of 2,3,5-Trichlorophenyl Methyl Sulfone, a Metabolite of 1,2,4-Trichlorobenzene, in the Induction of Hepatic Microsomal Drug-Metabolizing Enzymes by 1,2,4-Trichlorobenzene in Rats

2,3,5- and 2,4,5-trichiorophenyl methyl sulfides, 2,3,5- and 2,4,5-trichlorophenyl methyl sulfoxides, and 2,3,5- and 2,4,5-trichlorophenyl methyl sulfones (TCPSO 2Mes) were detected in the urine of rats dosed with 1,2,4-trichlorobenzene (TCB). After the administration of 1,2,4-TCB to rats, swift decreases in concentrations of 1,2,4-TCB in blood, liver, kidneys, and adipose tissue were observed. On the other hand, 2,3,5-TCPSO 2Me appeared in blood, liver, kidneys, and adipose tissue and remained detectable in the blood and the three tissues until 120 hr. The increases in the activities of aminopyrine N-demethylase and aniline hydroxylase and the contents of cytochromes P450 and b 5 in hepatic microsomes produced by 1,2,4-TCB occurred after increases in the hepatic concentration of 2,3,5-TCPSO 2Me. 2,3,5- and 2,4,5-TCPSO 2Me increased the above four parameters in rat liver microsomes. The inducing intensity of 2,3,5-TCPSO 2Me was much higher than that of 2,4,5-TCPSO 2Me. 2,3,5-TCPSO 2Me was considered to be a potent inducer and to play a principal role in the induction by l,2,4-TCB. When l,2,4-TCB was injected ip into bile duct-cannulated rats, little 2,3,5-TCPSO 2Me was detected in blood, liver, kidneys, and adipose tissue. In the antibiotic-pretreated rats dosed with 1,2,4-TCB, 2,3,5-TCPSO 2Me concentrations in the blood and the three tissues markedly decreased. These findings suggest that the formation of methylsulfonyl metabolites from 1,2,4-TCB depends largely upon the metabolism of some precursor(s) excreted in the bile by intestinal microflora. The increasing effects of 1,2,4-TCB administration on the activities of aminopyrine- and aniline-metabolizing enzymes and the contents of cytochromes P450 and b 5 in hepatic microsomes were not observed in the bile duct-cannulated rats. These findings provide evidence that the induction of drug-metabolizing enzymes by 1,2,4-TCB is not due to the action of 1,2,4-TCB itself but is due to its methylsulfonyl metabolite, 2,3,5-TCPSO 2Me.

Hepatic microsomal drug-metabolizing enzyme in aflatoxin B1-treated rats after feeding vegetable diet Amaranthus hybridus

The effect of vegetable diet on the drug-metabolizing enzymes after aflatoxin B1 treatment were studied in male rats for 30 d. The diets contained various levels of the leafy vegetable Amaranthus hybridus, 0 (Ah0), 200 (Ah200) or 600 (Ah600) g/kg, and the animals were given intraperitoneally injected aflatoxin B1 (either 0 or 0.2 mg/kg body weight) in propylene glycol every two days. After 10, 20, and 30 d, the animals were killed and their serum and hepatic microsomes prepared for the assay of enzymes. The group of rats fed diet containing 600 A. hybridus showed highest gain, whereas those fed diet without vegetable showed lowest weight gain. The cytochrome P-450 content of the liver, as well as the activity of aminoprine N-demethylase and that of aniline hydroxylase was high in the group fed Ah 600. When rats were given aflatoxin B1, the level of cytochrome P-450 decreased in group fed diet Ah600, showing a significant dietxaflatoxin B1 interaction. For UDPglucuronyltransferase, rats fed on diet containing 200 or 600g A. Hybridus /Kg diet showed the highest activity in this enzyme. After aflatoxin B1 treatment, group fed on diet Ah 0 showed a significant increase in the activity of UDPglucuronyltransferase (186 percent) after 30d. This was seen as being a sign of toxicity of aflatoxin B1 towards the rats fed on the above diet. This experiment emphasizes the ability of leafy vegetable A. hybridus in inducing hepatic liver drug-metabolizing enzymes through improvement of nutrient content of the diet.

Comparative assessment of the effect of aflatoxin B1 on hepatic dysfunction in some mammalian and avian species

1. Aflatoxin Bl (1.5 mg/kg body weight, i.p.) was administered to rats, mice, quail and chickens to examine the comparative effect on hepatic microsomal drug-metabolizing enzymes, cytosolic glutathione S-transferase and serum enzymes. 2. Administration ofaflatoxin B1 to rats resulted in a significant decrease in microsomal cytochrome P-450, NADPH-cytochrome C reductase, activities of aminopyrine N-demethylase, aniline hydroxylase, cytosolic glutathione S-transferase and liver glutathione content. However, no significant changes in these parameters were seen in mice. 3. Quail showed a significant decrease in the content of cytochrome P-450 and the activities of aminopyrine N-demethylase, aniline hydroxylase and cytosolic glutathione S-transferase. A similar treatment did not affect these biotransformation enzymes in chickens. 4. The activities of serum enzymes, sorbitol dehydrogenase, alanine aminotransferase and aspartate aminotransferase were increased significantly in rats and quail. Mice exhibited a significant increase in the activities of sorbitol dehydrogenase and aspartate aminotransferase, while chickens showed a significant increase only in alanine aminotransferase.

Inhibitory Effect of Cannabidiol Hydroxy-quinone, an Oxidative Product of Cannabidiol, on the Hepatic Microsomal Drug-Metabolizing Enzymes of Mice.

Cannabidiol hydroxy-quinone (CBDHQ) was identified as an air oxidation product of cannabidiol (CBD). The in vitro incubation of mouse hepatic microsomes with CBDHQ resulted in a decrease of cytochrome P-450 content. CBDHQ inhibited the hepatic microsomal drug-metabolizing enzymes of mice. This inhibitory effect was stronger than that of CBD. CBDHQ (150 microM) inhibited aniline hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase in the microsomes by 70, 52 and 77%, respectively, whereas the same concentration of CBD caused the inhibition by 39, 30 and 26%, respectively. CBDHQ (91.5 microM) significantly decreased total heme content by 21% and free SH groups by 11% in the microsomes. The results indicate that CBDHQ, which is an oxidation product of CBD, inhibits the hepatic microsomal drug-metabolizing enzymes through the decrease of cytochrome P-450 content.

Bioactivity of neolignans from fructus Schizandrae.

Fructus Schizandrae sinensis Baill, a traditional Chinese medicine, used as tonic and sedative, has been shown at the beginning of 70's to lower the elevated serum glutamic-pyruvic transaminase (SGPT) levels of patients suffering from chronic viral hepatitis. During past 20 years, a series of neolignans have been isolated and identified as effective principles. Pharmacological studies revealed that they increased liver protein and glycogen synthesis, antagonized liver injuries from CCl4 and thioacetamide. The mechanism of SGPT lowering was considered as a hepato-protective and membrane stabilize action, although inhibition of the activity of liver GPT may also be existed. It was found that some principles of Schizandrae have an inducing effect on hepatic microsomal drug-metabolizing enzyme system P-450, thus explained their anti-toxic, anti-carcinogenic and anti-mutagenic effects. A synthetic derivative compound of Schisandrin called DDB has most of the above mentioned actions now used widely in China as a hepato-protective drug with high effectiveness in normalizing liver functions and very low side effects. From natural Schisandrin to synthesized DDB, pointed out a successful way in the development of new drugs from natural products.

Formation of an Antibacterial Metabolite from a New Macrolide Compound 23-O-Benzyl-5-mycaminosyl-tylonolide (TMC-101), by a Hepatic Microsomal Drug-Metabolizing Enzyme System.

Upon incubation of 23-O-benzyl-5-mycaminosyl-tylonolide (TMC-101) with liver microsomes in the presence of an nicotinamide adenine dinucleotide phosphate-generating system, at least four metabolites were formed: two of them were also formed by an enzyme(s) in rat serum. One of the metabolites formed by liver microsomes possessed antibacterial activity comparable to TMC-101 as examined by bioautography using Micrococcus luteus ATCC 9341 as a tester strain. Incubation of TMC-101 with rat serum degraded most of the parent compound and did not form the active metabolite. The capacity of liver microsomes to produce the active metabolite was increased by pretreatment of rats with 3-methylcholanthrene, phenobarbital and polychlorinated biphenyl. The metabolite with the antibacterial activity was estimated not to be formed by the N-demethylation of TMC-101, and was chemically unstable.