Organophosphate detoxification related to induced hepatic microsomal enzymes of chickens

Detoxification of the organophosphate malathion in its activated form (malaoxon) was increased in livers of chickens given microsomal enzyme inducers (beta-naphthoflavone, 3-methylcholanthrene, butylated hydroxytoluene (BHT), or polychlorinated biphenyls). Positive correlations between inducer and microsomal enzyme activity were demonstrated for beta-naphthoflavone with demethylation of p-nitroanisole and for 3-methylcholanthrene and for BHT with cytochrome P450/448 and cytochrome b5. Malaoxon detoxification decreased in correlation with decreases in quantities of cytochrome P450/448 in birds fed a low-protein diet. Prediction of malaoxon detoxification was aided by using enzyme activities as dependent variables in the regression model, although only in birds given BHT were all of the 5 enzymes necessary for providing the best predictive model.     

Modulations of bovine hepatic microsomal metabolism of benzimidazoles by secondary plant metabolites

The study was aimed to estimate the effect of plant secondary metabolites present in ruminants diet and phytogenic feed additives on liver microsomal metabolism of albendazole and fenbendazole. The selected phytocompounds comprised of flavonoids (apigenin, quercetin) and saponins (hederagenin, medicagenic acid). The experiments were performed on liver microsomal fraction obtained from routinely slaughtered cows. The intensity of albendazole and fenbendazole metabolism in the presence of flavonoids and saponins was analyzed in equimolar concentration (100 μM). The obtained results revealed that both flavonoids and saponins intensify the metabolism of albendazole and fenbendazole in bovine microsomes. In the case of albendazole, apigenin and quercetin doubled the amount of degraded drug and the amount of produced albendazole sulfoxide. Additionally, both flavonoids increased the amount of produced albendazole sulfone. Saponins, hederagenin, and medicagenic acid intensified the degradation of albendazole (1.8‐fold) and the production of albendazole sulfoxide (twofold). Medicagenic acid inhibited the production of albendazole sulfone. In the case of fenbendazole, the degradation of the drug and the production of oxfendazole were increased four and five times in the presence of saponins and flavonoids, respectively. The enhancement of benzimidazoles’ metabolism caused by the studied plant metabolites could change pharmacokinetics and the efficacy of benzimidazoles’ treatment in cattle.     

Induction of hepatic microsomal enzymes in chickens effected by various persistent foreign materials]

Changes in the levels of microsomal proteins, in the activity of microsomal aniline hydroxylase, and in the effectivity of Thiopental were studied in chickens given the Czechoslovak-produced type of polychlorinated biphenyls - Delor 103. The increased activity of aniline hydroxylase and the decrease of Thiopental sleeping time in chickens exposed to the action of Delor 103 indicate that this preparation is able to induce liver microsomal enzymes in doses as low as 5 mg per kg of feed. The induction of liver microsomal enzymes appears to be an important factor, able to exercise a direct influence on the biotransformation of various biologically important substances in the organism of chickens.     

Maternal exposure to low doses of DES altered mRNA expression of hepatic microsomal enzymes in male rat offspring

Our previous studies demonstrated that prenatal diethylstilbestrol (DES) treatment disrupts steroidogenesis but induces high-level expression of androgen receptor (AR) mRNA to inhibit the disruption of spermatogenesis. This study examined which prenatal DES treatment influenced hepatic microsomal enzymes, CYP3A1, CYP2B1/2, CYP2C11, UGT2B1 (UDP-glucuronosyltransferase 2B1), and IGF-1 (insulin-like growth factor-1), in male rat offspring. DES treatment decreased the mRNA expression levels of CYP3A1 and CYP2B1/2, but did not alter the expression of CYP2C11. At 6 weeks, DES treatment increasd the mRNA expression levels of UGT2B1 and IGF-1. These results suggest that prenatal DES treatment alters two hepatic enzymes (CYP3A1 and CYP2B1/2) and IGF-1 mRNA expression levels to counteract the low level of testosterone, but this disrupted UGT2B1 mRNA expression reduces the testosterone level.     

Marek's disease vaccination, with turkey herpesvirus, and enrofloxacin modulate the activities of hepatic microsomal enzymes in broiler chickens

Chickens were vaccinated against Marek's disease intramuscularly at one day of age. Enrofloxacin was given ad libitum in the drinking water at concentrations of 50, 100 and 250 mg/L from 8 days to 13 days of age when the animals were killed and the activities of cytochrome P-450 enzymes in the liver were measured. Vaccinated non-treated chickens served as a positive control. A negative control group was neither vaccinated nor treated. Vaccination decreased the activity of aniline hydroxylase and ethylmorphine N-demethylase in the positive control group. Subsequent application of enrofloxacin in the lowest concentration (50 mg/L) decreased, while that given at the highest level (250 mg/L) significantly increased the activity of the same microsomal enzymes. Relative liver weights and concentrations of proteins in 9000 x g supernatant were not affected by vaccination or treatment.     

Short-term regulation of hepatic triacylglycerol metabolism by insulin and glucagon

This paper presents a review of our current knowledge of short-term regulation of triacylglycerol metabolism by insulin and glucagon in isolated rat hepatocytes. Insulin is devoted to rapidly improve the lipogenic climate of the hepatocyte. The hormone stimulates glycolysis, the conversion of pyruvate into acetyl-CoA, the synthesis of fatty acids and their esterification. The opposite pathways, hydrolysis of triacylglycerols and fatty acid oxidation, are depressed by insulin. Glucagon does all but deteriorate the lipogenic climate within the liver cell as the hormone inhibits triacylglycerol synthesis and stimulates the breakdown of triacylglycerols.     

Characterisation of hepatic microsomal glucose-6-phosphatase from broiler chickens

1. The hepatic glucose-6-phosphatase (G-6-Pase) kinetic variables from chickens were studied in intact and disrupted microsomes using two substrates: glucose-6-phosphate (G-6-P) and pyrophosphate (PPi). They were studied from embryonic life to 51 d of age. 2. The phosphohydrolase activity studied in the broiler chicken liver microsomes corresponds to a true glucose-6-phosphatase. 3. The enzyme VMAX with both substrates in intact and disrupted microsomes showed 2 maxima: one in 19-d-old embryos and the other in 9-d-old chickens. Pyrophosphatase (PPase) VMAX in intact microsomes was higher than that of the G-6-Pase at all ages studied, except in 12 d embryos and 3-d-old chicks. In disrupted microsomes the VMAX of both enzymatic activities were similar. The G-6-Pase latency was high in the 19-d-old embryos and 51-d-old chickens. 4. The KM for PPi and G-6-Pase decreased when microsomes were disrupted. In intact microsomes the G-6-P KM was low in embryos and 3-d-old chicks and later increased. On the other hand, the PPi KM in intact microsomes showed little change during the animal's life and was lower than that of G-6-P. In disrupted microsomes the KM for both substrates were similar. 5. These results suggest a sequential incorporation of the G-6-Pase system components in the endoplasmic reticulum.     

Macrolide antibiotics, drug interactions and microsomal enzymes: implications for veterinary medicine

The macrolide group of antibiotics includes natural members, pro-drugs and semi-synthetic derivatives, thus named because they are composed of a large aglycone ring (from 14 to 16 carbon atoms), to which are attached several sugars. Some of them are amino-sugars, containing a diethylamino, tertiary amine function. A number of antibiotics, including erythromycin, oleandomycin, triacetyl-oleandomycin (troleandomycin), carbomycin, spiramycin, tylosin, rosamicin, azithromycin, clarithromycin, dirithromycin and others, are members of this group. On a comparative basis, erythromycin and oleandomycin are similar, with the same basic 14-carbon lactone ring and side chain sugars. The remaining compounds contain a basic 15- or 16-carbon lactone ring and one or two side-chain sugars. Most of the macrolides are produced by Streptomyces spp bacteria. An exception is rosamicin, which is produced by Micromonospora. Clarithromycin and azithromycin are new semi-synthetic derivatives of erythromycin.     

Hepatic drug metabolism and adverse hepatic drug reactions.

Drugs and other chemicals are usually metabolized in the liver in the drug-metabolizing enzyme system. The metabolites sometimes bind with cellular macromolecules and injure the cell directly or serve as new antigens to create immunologic injury in a delayed fashion. The immediate or toxic injury is dose-dependent, predictable and zonal in the liver lobule, usually in the central region. Carbon tetrachloride intoxication and acetaminophen overdose are examples of injury resulting from microsomal metabolism. Other injuries related to microsomal metabolism are those produced by vinyl chloride in polymerization plant workers and by methotrexate in psoriatics or leukemic children. Most adverse drug reactions affecting the liver and producing jaundice are unpredictable, delayed in onset, and only hypothetically related to microsomal metabolism in some instances. The two main types are cholestasis and viral-hepatitis-like. The former may be in a pure form, in which case it may be partly dose-dependent, or in a form mixed with hepatitis. Many drugs produce cholestasis in a small percentage of persons, and because the reaction is benign, albeit prolonged at times, such drugs continue to be used. The viral-hepatitis-like reaction involves few drugs and affects few persons, but can be fatal. The recognition that chronic hepatitis can be caused by drugs such as oxyphenisatin, alpha-methyldopa, and isoniazid has added a new dimension to the clinical problem of adverse drug reactions, which may extend to widely used and commonly available agents like aspirin.     

微粒体甘油三酯转运蛋白脂代谢作用及表达与调节

从微粒体甘油三酯转运蛋白(MTP)的活性与多态性、在脂代谢中作用、表达与调节等方面综述了MTP是一种重要的脂质转运蛋白。MTP的活性、基因表达状态是控制极低密度脂蛋白(VLDL)合成、装配和分泌速率的重要因素,研究MTP基因表达与调节对预防动物脂肪肝,提高家畜家禽生产品质,探讨人类脂类代谢疾病和心血管疾病等重要疾病形成机制,以及防治这些疾病具有重要临床意义。     

Effect of pretreatment with hepatic microsomal enzyme inducers on the toxicity of diazinon in calves

The pretreatment of calves with a single dose of 10 mg kg-1 dieldrin or 21 daily doses of 10 mg kg-1 phenobarbitone increased the toxicity of diazinon as reflected by the development of more severe clinical signs and greater depression in whole blood cholinesterase activity in the pretreated calves. Induction by dieldrin or phenobarbitone of the hepatic microsomal enzyme amidopyrine-N-demethylase was also accompanied by a concurrent rise in the liver carboxylesterase activity.     

2种紫花苜蓿氮代谢及其关键酶(NR、GS)活性差异研究

为探究不同紫花苜蓿氮代谢差异及氮代谢差异的生理机制,采用盆栽砂培法,通过对2个具有典型特征的紫花苜蓿品种(LW6010和陇东苜蓿)在2个氮素水平及3个生育时期下其氮代谢产物及氮代谢酶活性差异进行研究,探讨氮代谢产物与氮代谢酶活性的相互关系。结果表明:LW6010和陇东苜蓿在N210水平下其干物质重、氮含量、氮积累量及硝酸还原酶(NR)、谷氨酰胺合成酶(GS)活性均高于N21。在2个氮水平下,LW6010的干物质重、NR和GS活性均显著大于陇东苜蓿,而LW6010的氮含量显著低于陇东苜蓿。其中,LW6010的NR活性比陇东苜蓿在N210和N21下分别高24%和15%(苗期)、31%和40%(现蕾期)、20%和11%(盛花期);GS活性分别高30%和29%(苗期)、33%和20%(现蕾期)、7%和14%(盛花期)。在苗期和盛花期时,LW6010的氮积累量显著大于陇东苜蓿,而在现蕾期差异不显著。LW6010的氮积累量在N210下各生育期分别比陇东苜蓿高25%,3%和16%,而在N21下LW6010的氮积累量在苗期和盛花期下比陇东苜蓿高45%和12%。同时,紫花苜蓿干物质重、氮积累量、NR活性与GS活性呈极显著正相关关系。综上分析,紫花苜蓿的不同品种在不同氮素水平下其氮代谢能力不同,不同紫花苜蓿品种间氮代谢具有差异;LW6010较陇东苜蓿具有较好的氮代谢能力;NR和GS活性可为不同紫花苜蓿氮代谢差异评价提供参考。     

Dexamethasone and colostrum feeding affect hepatic gluconeogenic enzymes differently in neonatal calves

Plasma glucose concentrations in neonates are influenced by colostrum feeding and by glucocorticoids. We have tested whether a high-glucocorticoid status after birth, as well as colostrum feeding, influences glucose metabolism in association with changes of hepatic expression and activities of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and pyruvate carboxylase (PC; EC 6.4.1.1) in neonatal calves. Calves (n = 14 per group) were fed either colostrum or a milk-based formula with nutrient and energy contents similar to colostrum. Half the calves in each feeding group were treated with dexamethasone (DEXA; 30 microg/[kg BW x d]). Pre- and postprandial blood samples were taken on d 1, 2, 4, and 5 and liver samples were collected on d 5 of life. Dexamethasone treatment increased (P < or = 0.05) plasma concentrations of glucose, insulin, and glucagon more in colostrum-fed than in formula-fed calves but increased (P < or = 0.05) urea concentrations and decreased (P < or = 0.05) concentrations of NEFA, ACTH, and cortisol independent of colostrum vs. formula feeding. Colostrum feeding increased (P < 0.05) plasma glucose, but decreased (P < 0.05) plasma urea concentrations. Glucagon-to-insulin ratios in DEXA-treated and colostrum-fed calves were decreased (P < 0.05). Dexamethasone treatment decreased hepatic mRNA levels and activities of PC (P < 0.001 and P < 0.10) and activities of PEPCK (P < 0.001) but increased (P < 0.001) the glycogen content. Colostrum feeding increased (P < 0.05) mitochondrial PEPCK mRNA levels and PEPCK activities in calves not treated with DEXA but decreased (P < 0.1) amounts of PC mRNA. In conclusion, increased plasma glucose concentrations after DEXA treatment were not associated with a stimulation of hepatic gluconeogenic enzyme activities; however, colostrum feeding probably raised plasma glucose concentrations because of increased hepatic gluconeogenic activities.     

Effects of two infectious bursal disease vaccine virus strains on hepatic microsomal enzyme activities in chickens

The influence of two infectious bursal disease vaccines on the activities of hepatic microsomal enzymes aniline hydroxylase, ethylmorphine N-demethylase, NADPH-cytochrome c reductase, aryl sulphotransferase and p-nitrophenol UDP-glucuronyltransferase was investigated in chickens. The vaccines contained attenuated Winterfield 2512 and VMG-91 strains, respectively. The activities of enzymes were determined on postvaccination days 0, 2, 5 and 7. At the same time, post-mitochondrial supernatant, cytosolic and microsomal pellet protein concentrations were determined. As expected, the antibody titres against infectious bursal disease virus in the serum were increased in both tested groups in relation to each administered vaccine. Using RT-PCR, the presence of the VP2 gene fragment of virus in the liver of chicken was demonstrated 4 and 6 h after vaccination. The results of this study suggest that the two commercial vaccines modulate the activities of five enzymes tested, and that the two attenuated vaccines applied triggered induction and/or inhibition of phases I and II of biotransformation enzyme activities.     

Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs

We examined inhibitory effects of ofloxacin (OFX), orbifloxacin (OBFX), ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX) on cytochrome P-450 1A (CYP1A) activities using hepatic microsomes from four beagle dogs. Ethoxyresorufin O-de-ethylation was referred as CYP1A activities. All the fluoroquinolones inhibited the reaction in a noncompetitive manner. The determined inhibitory constants were the followings; 10.1 +/- 3.8 mM for OFX, 6.43 +/- 2.01 mM for OBFX, 0.726 +/- 0.134 mM for CFX, 4.06 +/- 1.19 mM for EFX and 4.75 +/- 1.63 mM for NFX respectively. As these values are >100-fold of plasma concentrations after a clinical single dose of the fluoroquinolones, it is suggested that the inhibitory effect on CYP1A activities is not so high to elicit drug-drug interaction with CYP1A substrates, when these fluoroquinolones are co-administered. Mechanism based inhibition was also examined in this study. Of the five fluoroquinolones examined, OFX, OBFX and CFX had this inhibition manner. As this inhibition is irreversible, inhibitory effects of the three fluoroquinolones may accumulate, when they are repeatedly administered. Therefore, OFX, OBFX and CFX may result in substantial drug-drug interaction with a CYP1A substrate even in clinical states. As EFX is metabolized to CFX in the body, it may also have the same possibility.     

Comparison of the effects of Sesbania drummondii on the hepatic microsomal monooxygenase systems of chickens and rats

Sesbania drummondii, a toxic leguminous shrub found throughout the southeastern United States, induces different responses in chicken vs rat hepatic microsomal monooxygenase systems. Groups of 4- to 8-week-old Sprague-Dawley rats and White Leghorn chickens were given extracts of S drummondii by gavage for 3 days. Doses, which were 0.4 and 0.8% of daily body weights, respectively, for the rats and chickens, were adjusted to induce similar clinical lesions in the 2 species. The hepatic microsomal monooxygenase systems of control and treated animals were compared, using cytochrome P-450 content, cytochrome b5 content, NADH- and NADPH-cytochrome c-reductase activity, and 6 cytochrome P-450 mediated enzyme activities. Increases of twofold in the cytochrome P-450 content, NADPH-cytochrome c-reductase, aminopyrine-N-demethylase, aniline hydroxylase, ethoxycoumarin-O-deethylase, and aryl hydrocarbon hydroxylase activities; fourfold in the aldrin epoxidase activity; and 15-fold in the ethoxyresorufin-O-deethylase activity were observed in the S drummondii-treated chickens. In contrast, the treated rats had nearly twofold decreases in these values, suggesting a species-specific effect of S drummondii on microsomal monooxygenase systems, ie, induced with S drummondii.     

Effect of short-term fasting on hepatic steroid hormone metabolism in cows

In the present study, the effect of 4-day fasting on steroid hormone metabolism in the liver and secretion of LH was examined in cows. Six non pregnant, dry Holstein cows were used. The estrous cycle was synchronized in all cows using CIDR-Ovsynch. Cows were allocated to a control group (n=3) and a fasting group (n=3). In the fasting group, cows were fasted for four days from day -4 to day -1 (day 0=day of 2nd GnRH injection) but otherwise were fed ad libitum. The experiment was repeated in a crossover design after an interval of about one month. The peripheral progesterone (P(4)) concentration in the fasting group was significantly higher than in the control group on day -1 and 0. The peripheral estradiol-17β concentration in the fasting group was also significantly higher than in the control group on day -1 and 0. The portal vein P(4) concentration in the fasting group was significantly higher than in the control group. On day 0, there was no difference in LH secretion between groups. The mean percentages of lipid droplets in liver cells in the fasting group were significantly higher than in the control group on day 0. These results suggest that short-term fasting leads to reduced hepatic steroid hormone metabolism by accumulation of fat in the liver, which causes high peripheral steroid hormone concentrations.