The effect of dietary energy and protein deficiency on drug metabolism

Summary The influence of a diet deficient in energy or protein on hepatic oxidation (Phase I reactions) and glucuronidation (Phase II reactions) in man has been examined. Nine healthy volunteers were fed an energy deficient diet (daily energy intake 4.3 MJ; daily protein intake 0.94 g/kg) and a protein deficient diet (daily energy intake 11.4 MJ; daily protein intake 0.31 g/kg) in random order. The control energy and protein intakes were 12.0 MJ and 1.52 g/kg, respectively. Each test diet period lasted 12 days. On Day 10, antipyrine 1000 mg and metronidazole 500 mg were given and elimination in saliva was determined.The metabolism of neither drugs was changed during the two dietary interventions, nor was their clearance to metabolites. On Day 12, the metabolism of oxazepam 15 mg was studied. The energy deficient and the protein deficient diet reduced the clearance rate of oxazepam by 20.3%, and 14.1% respectively. The elimination half-life was prolonged by 17.4% after the former and by 11.4% after the latter diet.Thus, both a low energy and a low protein intake decreased the glucuronidation of oxazepam, whereas no effect was observed on the rate of oxidation, expressed as the metabolism of antipyrine and metronidazole.The study was supported by the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe Islands and Greenland, and Rhône Poulenc Pharma Norden A/S.     

Growth, liver lipid and blood amino acids in rats fed ethanol with an adequate diet

The weight, histology and RNA, DNA, protein and lipid content of the liver and arterial and portal plasma amino acid concentrations were determined in male Sprague-Dawley rats fed a liquid diet which met AIN-76A standards with 36% of the calories supplied by ethanol. The dietary components of the dry mixture in percentages by weight included 20% casein, 22% sucrose, 43% dextrin, 5% corn oil, vitamins, minerals and other dietary factors. For feeding these were suspended in distilled water containing 2.5% xanthan gum with or without ethanol to supply 1 kcal/ml. The feeding method employed perforated neoprene discs floated on top of the suspended diet to control evaporative losses. Animals were pair fed or ad libitum fed for 8-10 weeks. Gain/feed ratios were virtually identical for ethanol-fed rats and their pair-fed controls. Ethanol intake of ad libitum fed rats averaged 14.8, 10.3 and 7.4 g/kg BW/day after 1, 5 and 10 weeks, respectively. No chemical or histological evidence of liver fat accumulation or significant differences in arterial or portal amino acid concentrations were detected in animals fed ethanol. The lack of apparent ethanol toxicity is discussed in relation to the results of others and to our earlier report of increased orotic acid excretion by ethanol-fed rats.     

Alcohol withdrawal reactions after chronic intake of chlordiazepoxide and ethanol

Withdrawal reactions were compared in C57BL/6J mice, which had been fed an ethanolic liquid diet containing chloridazepoxide (CDP, 3.2 or 6.4 mg/100 ml, group B or C, respectively) with those which had been administered an ethanol diet alone (group A) for 15 days. Group A showed a significantly more pronounced decrease in rectal temperature (4 to 10 hr) and a higher withdrawal score (4 to 14 hr) than mice in groups B and C. The differences in withdrawal signs still persisted even after mice were fed an ethanol diet without CDP for one extra day before withdrawal. The presence of metabolites of CDP in the blood during withdrawal could only account for a minor contribution to the protective effect. Our data are more suggestive of an increased rate of ethanol metabolism leading to lower blood alcohol levels during diet intake period as being the major factor. However, we cannot rule out the alternative possibility that CDP or its metabolites might interfere with the development of tolerance to and physical dependence on alcohol.     

LONG-TERM EFFECTS OF HIGH CALORIE SUCROSE-ENRICHED DIET AND STREPTOZOTOCIN-INDUCED DIABETES ON INSULIN RESISTANCE IN SPONTANEOULY HYPERTENSIVE RATS§

1. The effects of two experimental manipulations on insulin resistance were compared in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Rats were fed a high calorie sucrose-enriched diet (high calorie diet) or were made diabetic by the injection of streptozotocin (STZ). 2. After treatment with the high calorie diet for 8 weeks, blood pressure increased in SHR, but not in WKY rats. In contrast, STZ treatment decreased blood pressure in SHR, but increased it in WKY rats. 3. Plasma glucose levels during oral glucose loading were higher in SHR than in WKY rats. Glucose tolerance was impaired to a greater extent by both the high calorie diet and STZ in SHR than in WKY rats. Hyperinsulinaemia induced by the high calorie diet was severe in SHR compared with WKY rats. 4. Abnormalities in lipid metabolism induced by a high calorie diet or STZ-induced diabetes were more marked in SHR than in WKY rats. 5. Steady-state plasma glucose levels in the insulin suppression test were higher in SHR than in WKY rats, both of which were treated by either the high calorie diet or STZ. These findings indicate that insulin-stimulated glucose uptake by high calorie diet or STZ-induced diabetes was impaired to a greater extent in SHR than in WKY rats. 6. It is concluded, therefore, that SHR fed on high calorie diet or SHR with STZ-induced diabetes are suitable models to study the effects of antihypertensive treatment on glucose tolerance, insulin resistance or lipid metabolism as well as blood pressure.     

Altered sensitivity to ethanol following prenatal exposure to barbiturate

Female mice (genetically heterogeneous stock) were fed milled mouse food containing 3 g/kg phenobarbital (PhB) and water as their only nutritional source from gestation days 9–18. Control dams received milled food and water. Blood PhB levels of treated females and fetuses were 40–200 g/ml. At the age of 50 days, male offspring were injected with 3.5 g/kg ethanol. Sleep time was monitored and in randomly selected individuals, brain ethanol levels were determined upon awakening. To assess the rate of metabolism in the treated and control offspring, blood ethanol levels were determined in other randomly selected individuals at 60 and 120 min post-injection. Offspring who received PhB prenatally were resistant to the hypnotic effects of ethanol as evidenced by their 33% shorter sleep time compared to controls (P<0.001). The brain ethanol levels upon awakening were higher than control in the offspring born to the barbiturate-treated mothers (P<0.001), indicating that the resistance to ethanol was due to factors residing within the central nervous system.     

Increased serum and testicular androgen levels in F1 rats with lifetime exposure to soy isoflavones

The consequences of dietary soy isoflavones on serum and testicular androgen levels were examined in F1 male rats from a multigeneration study investigating the effects of diets varying in isoflavone content. Rats were fed either a soy-free casein based diet (AIN93G) or a diet in which alcohol-washed soy protein replaced casein as the protein source and to which increasing amounts of Novasoy, a commercially available isoflavone supplement were added. Analysis of these diets showed that the isoflavone content in each diet was 0 (diet 1; casein based control), 31.7 (diet 2; alcohol-washed soy-based diet control), 36.1 (diet 3), 74.5 (diet 4), 235.6 (diet 5) and 1046.6 (diet 6) mg total isoflavones/kg pelleted diet. The levels of isoflavones in diet 1 would represent a daily intake level of 0 mg isoflavones, diets 2 and 3 estimate a low soy-containing human diet (e.g. North American), diet 4 would correspond to Asian diets (e.g. Japanese) or adult humans taking isoflavone supplements, diet 5 approximates the isoflavone intake by babies fed soy based infant formula and diet 6 approximates fivefold the intake levels by babies or 10-fold the intake levels of adults consuming high isoflavone containing diets. Serum testosterone (T) from F1 male rats sacrificed on postnatal days (PND) 28, 70, 120, 240 and 360 were low at PND 28 (0.4 ng/ml), increased approximately five to sixfold at PND 70 (2.5-3.0 ng/ml) and thereafter declined to a steady state level of approximately 1 ng/ml by PND 120. However, rats on diets 5 and 6 demonstrated altered serum testosterone profiles such that at days 120, testosterone levels remained significantly elevated at approximately 3 ng/ml (P < 0.05). Serum dihydrotestosterone levels exhibited similar profiles and the levels in PND 120 rats on diet 5 or 6 were also significantly elevated (two to threefold, P < 0.05). The intra-testicular testosterone concentration in rats on diet 5 was also elevated at PND 120 compared with diet 1 (P < 0.05). These findings show that F1 male rats continuously exposed to a mixture of dietary soy isoflavones from conception onwards exhibit altered serum and testicular androgen profiles.     

Effects on the fetus of maternal benomyl exposure in the protein-deprived rat

The separate and combined effects of protein deprivation and benomyl [(methyl 1-butylcarbomoyl)-2-benzimidazole carbamate] exposure were studied in the pregnant rat fed a diet containing 24% (control) or 8% (deficient) casein throughout gestation. Within each diet group, subgroups were gavaged at 31.2 mg/kg body weight with benomyl or corn-oil carrier only on d 7-16 or 7-21 of gestation. No effects on the skeleton were seen. Benomyl exposure in the last 2 wk in dams fed the 24% casein diet resulted in a high incidence of fetal brain anomalies. This effect did not occur in those with benomyl exposure during the period of organogenesis only and was reduced in groups fed the protein-deficient diet. Exposure to benomyl in the last 2 wk in the protein-deprived rat resulted in a decrease in the weight of the fetal heart in excess of that attributable to diet alone. Lungs were a smaller portion of body weight in fetuses of benomyl-treated dams in both diet groups. The teratogenic effect on the brain in animals exposed to benomyl in wk 2 and 3 of gestation suggests that screening for teratogenic effects during organogenesis only may be insufficient.     

Influence of dietary protein on the response of rats receiving toxic levels of warfarin

Toxic doses of racemic [¹⁴C]warfarin (3-(α-acetonylbenzyl)-4-hydroxycoumarin) were administered (0.8 mg/kg, po) for 5 days to rats fed one of three different purified diets, 25% casein, 8% casein, and casein-free. Four rats from each dietary group were bled at 6, 30, 54, 78, and 102 hr after the initial dose. Rats consuming a casein-free diet maintained higher total plasma warfarin levels than rats fed a 25 or 8% casein diet. Additionally, percentage free warfarin levels of 0% casein rats were greater than those of 25 and 8% groups through the first 78 hr. An increase in percentage unbound drug was therefore most likely associated with a decrease in total plasma clearance. The protein-free rats had a more rapid increase in prothrombin time and lower plasma albumin levels than rats fed either a 25 or 8% casein diet. A significant correlation was found between the percentage free fraction of warfarin and the prothrombin response in each of the three dietary groups. A negative correlation was found between percentage free plasma warfarin and plasma albumin concentration in each of the three dietary groups. A correlation was found between total plasma warfarin and prothrombin time for the rats on the 0% protein diet. It was concluded that the quantity of dietary protein was an important factor in determining the response of rats to toxic levels of warfarin.     

益气复脉注射液与银杏叶提取物注射液治疗急性脑梗死的疗效比较

目的:比较益气复脉注射液与银杏叶提取物注射液治疗急性脑梗死的疗效和安全性。方法:将140例急性脑梗死患者按随机数字表法均分为对照组和研究组。两组患者均给予鼻管吸氧、鼻饲流质饮食、低脂饮食、促脑细胞代谢药、抗脑水肿、控制血压、防止感染等常规治疗。在此基础上,对照组患者给予银杏叶提取物注射液25 ml加入5%葡萄糖注射液250 ml中静脉滴注,每日1次;研究组患者给予益气复脉注射液40 ml加入5%葡萄糖注射液200 ml中静脉滴注,每日1次。两组患者疗程均为14 d。比较两组患者的临床疗效,治疗前后脑梗死体积、神经功能缺损(NFDS)评分、白细胞介素(IL)-6、IL-8、C反应蛋白(CRP)水平及不良反应发生情况。结果:治疗后研究组患者总有效率显著高于对照组,两组比较差异有统计学意义(P<0.05)。治疗前两组患者各项指标比较,差异均无统计学意义(P>0.05);治疗后两组患者NFDS评分、IL-6、IL-8、CRP均显著低于同组治疗前,且研究组低于对照组,脑梗死体积大于同组治疗前,但研究组增加的幅度低于对照组,差异有统计学意义(P<0.05)。研究组患者不良反应发生率显著低于对照组,两组比较差异有统计学意义(P<0.05)。结论:益气复脉注射液治疗急性脑梗死较银杏叶提取物注射液疗效更显著,且安全性较好。     

Effects of cysteine on the pharmacokinetics of itraconazole in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of itraconazole were investigated after intravenous, 20 mg/kg, and oral, 50 mg/kg, administration of the drug to control rats (fed for 4 weeks on 23% casein diet) and rats with PCM (protein-calorie malnutrition, fed for 4 weeks on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). After intravenous administration of itraconazole to rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of itraconazole was significantly greater (3580 compared with 2670 and 2980 microg min/ml) than those in control rats and rats with PCMC (the values between control rats and rats with PCMC were not significantly different). The above data suggested that metabolism of itraconazole decreased significantly in rats with PCM due to suppression of hepatic microsomal cytochrome p450 (CYP) 3A23 in the rats. The results could be expected since in rats with PCM, the level of CYP3A23 decreased significantly as compared to control. Itraconazole was reported to be metabolized via CYP3A4 to several metabolites, including hydroxyitraconazole, in human subjects. Human CYP3A4 and rat CYP3A1 (CYP3A23) proteins have 73% homology. By cysteine supplementation (rats with PCMC), the AUC of itraconazole was restored fully to control levels.     

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of chlorzoxazone (CZX) and one of its metabolites, 6-hydroxychlorzoxazone (OH-CZX), were investigated after intravenous administration of CZX, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of OH-CZX (436 compared with 972 microgmin/ml) and the percentages of intravenous dose of CZX excreted in 8-h urine as OH-CZX (20.2 compared with 38.5%) were significantly smaller than those in control rats. The above data indicated that the formation of OH-CZX from CZX decreased significantly in rats with PCM due to a significant decrease in chlorzoxazone-6-hydroxylase activity (328 compared with 895 pmol/min/mg protein) in the rats. The results were expected since in rats with PCM, hepatic CYP2E1 expression and its mRNA levels decreased significantly as compared to control, and CZX was metabolized to OH-CZX primarily by CYP2E1 in rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters restored fully (hepatic microsomal chlorzoxazone 6-hydroxylation activity based on both mg protein and nmol CYP450) or partially (total body clearance and apparent volume of distribution at steady state of CZX, and AUC, terminal half-life and 8-h urinary excretion of OH-CZX) to control levels.     

瘦素在2型糖尿病大鼠肾脏病变发生发展中作用的探索

目的探讨瘦素(leptin)在糖尿病肾脏病(DN)变发生发展中的作用。方法雄性Wistar大鼠70只,随机分为实验组和对照组,实验组40只,喂以高热量饲料2个月后,腹腔注射链脲佐菌素(STZ)30mg/kg;对照组30只,喂以普通饲料2个月后,腹腔注射等体积的枸橼酸缓冲液。两组分别于注射前、注射后1、2、3和6个月各处死6只,取血测定血清瘦素、胰岛素水平等,光镜电镜观察肾脏形态学改变。结果成模后1月后肾小球体积开始增大,2月更明显,3月及6月体积显著下降;成模后2月出现明显蛋白尿,肾小球基底膜3月时就已显著增厚,6月时更为严重;瘦素水平在高热量饮食2月后即较对照组显著增高(P<0.01),在注射STZ后1个月时由于体重的下降而较前有所下降,但仍高于对照组(P<0.01),以后随着病程的进展呈逐渐升高趋势。结论进一步证明瘦素可能是促进糖尿病肾脏病变的发生、发展的因素之一。     

Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats

Objectives Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low‐protein diet. Methods Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100 mg/kg per day) for the last 5 days. Tolbutamide was co‐administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12 h and the activity of hepatic cytochrome P450s were determined at 12 h after dosing. Key findings There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low‐protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein‐restricted rats. Conclusions The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low‐protein diet.     

不同质量蛋白质对肾损害大鼠钙平衡的影响

目的：研究大豆蛋白对肾损害大鼠钙平衡的影响。方法：选择3月龄健康雄性SD大鼠40只，按体质量从小到大排序采用完全随机化原则分为4组，每组10只。标准饲料对照组：喂食含有14％酪蛋白饲料；大豆蛋白饲料组：喂食含有14％大豆分离蛋白饲料；混合饲料Ⅰ组：喂食含有7％酪蛋白加7％大豆分离蛋白饲料；混合饲料Ⅱ组：喂食含有7％酪蛋白加14％大豆分离蛋白饲料。实验期用腺嘌呤灌胃共21天建立肾损害大鼠模型，各组大鼠喂养相应饲料6周。测量指标：钙摄入量、尿钙、粪钙、血肌酐、尿素、白蛋白、钙、磷，骨钙。结果：大豆蛋白饲料组和混合饲料I组实验检测项目无明显统计学差异，与另外两组相比，血肌酐、尿素、磷低，血钙、钙表观吸收率、钙储留量和骨钙高，差异有统计学意义（P〈0．05）。结论：蛋白质含量水平在14％条件下，含大豆蛋白的饲料更有助于促进钙平衡。‘     

Effect of protein deficiency on the inducibility of the hepatic microsomal drug-metabolizing enzyme system—II: Effect on enzyme kinetics and electron transport system

Male, weanling rats divided into three groups were maintained for 15 days on a semipurified diet containing either 5% casein fed ad lib. (group 1), 20% casein pair-fed to group 1 (group 2), or 20% casein fed ad lib. (group 3). After each group was further subdivided, animals were injected i.p. on days 11–14 with either 0.9% saline or phenobarbital (80 mg/kg) in 0.9 % saline. Twenty-four hr after the last injection, animals were decapitated and liver microsomes were prepared. Apparent V_max and apparent K_m kinetic constants were determined for ethylmorphine and aniline. The V_max per milligram of microsomal protein was 64–66 per cent lower in the protein-deficient group. Equivalent reductions of the content of cytochrome P-450 and activities of cytochrome P-450 and c reductases were also observed. Phenobarbital induction increased specific enzyme activities (V_max per milligram of microsomal protein) in all groups with slightly greater percentage increases seen in the protein-deficient animals. Increases were also noted for the cytochrome P-450 content and cytochromes P-450 and c reductase activities. It was suggested that phosphatidylcholine and cytochrome P-450 both play important roles in the kinetics of metabolism determined after protein deficiency or phenobarbital induction, or both.     

Effect of dietary fat upon ethanol metabolism in rats

The effect of dietary fat upon ethanol metabolism was studied in rats. Wistar strain male rats were divided into four groups according to diet, namely alcohol-high fat, alcohol-low fat, control-high fat, and control-low fat. After 4 weeks of feeding, blood ethanol levels following an intraperitoneal injection of 0.2 g ethanol/100 g of body weight were measured. The disappearance rate of blood ethanol was faster and the metabolic rate of ethanol was significantly greater in the alcohol-high fat group compared to the alcohol-low fat or non-alcoholic groups. Microsomal enzymes, such as the microsomal ethanol-oxidizing system, aniline hydroxylase. and glucose-6-phosphatase, were significantly higher in the alcohol-high fat group than in the alcohol-low fat or non-alcoholic groups. The ethanol uptake rate of the isolated perfused liver was increased significantly in the alcoholic groups. In the alcoholic rats, the high fat group showed significantly higher uptake than the low fat group. Although the ethanol uptake rate after 4-methylpyrazole treatment was not significantly different among the four groups, its fraction of the total ethanol uptake was increased significantly in the alcohol-high fat group. These results suggest that high fat diets accelerate ethanol metabolism through the microsomal ethanoloxidizing system.     

绞股蓝干预食饵兔动脉粥样硬化过程中对内皮素-1和C反应蛋白的影响研究

目的研究清热解毒中药绞股蓝干预食饵兔动脉粥样硬化(As)过程中对内皮素-1(ET-1)和C反应蛋白(CRP)的影响。方法40只日本大耳白兔随机分为绞股蓝干预组(A组)、辛伐他汀干预组(B组)、高脂模型组(C组)、正常对照组(D组),分别喂饲高脂饵料(标准饵料92.5%+2%胆固醇+2%蛋黄+3.5%猪油)+绞股蓝5 g/kg、高脂饵料+辛伐他汀5 mg/kg、高脂饵料、标准饵料。实验前和实验后3、9周检测甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、ET-1、CRP。观察主动脉病理学形态。结果①病理学:A组、B组、C组、D组的粥样硬化斑块/内膜面积比分别为(31±5)%、(32±6)%、(60±9)%、0,A组、B组与C组间比较差异有统计学意义(P<0.01);A组、B组、C组、D组的内膜/中膜厚度比分别为(40±16)%、(41±15)%、(70±12)%、0,A组、B组与C组间比较差异有统计学意义(P<0.01)。②ET-1:A组、B组、C组ET-1水平较饲养前明显上升(P<0.01),A组、B组显著低于C组(P<0.01)。③CRP水平:饲养后A组、B组、C组CRP渐升,与饲养前比较差异有统计学意义(P<0.01),A组、B组CRP低于C组(P<0.01)。④血脂:A组、B组、C组随饲养时间延长,TG、TC、LDL-C渐升,与饲养前比较差异有统计学意义(P<0.05,P<0.01),A组、B组HDL-C与饲养前比较差异有统计学意义(P<0.01),A组、B组TG、TC、LDL-C低于C组(P<0.05,P<0.01)。结论清热解毒中药绞股蓝食饵对兔As与辛伐他汀有相似的干预作用,干预作用与调节保护内皮细胞、抑制炎症反应、调节血脂代谢有关。     

Role of alcohol dehydrogenase in the swift increase in alcohol metabolism (SIAM). Studies with deer mice deficient in alcohol dehydrogenase

Previous studies have shown that rates of ethanol metabolism increase markedly 2-4 hr after the administration of ethanol in rats and in four inbred strains of mice. This phenomenon, called the swift increase in alcohol metabolism (SIAM), also exists in humans. To determine whether alcohol dehydrogenase (ADH) is necessary for the SIAM response, we compared ethanol metabolism in two strains of the deer mouse, Peromyscus maniculatus. One strain lacks alcohol dehydrogenase (ADH-negative), whereas the other strain has normal ADH levels (ADH-positive). Rates of ethanol elimination were determined after a single intraperitoneal injection of ethanol at different doses (0.5 to 3.0 g/kg) and also after both strains were exposed to various levels of ethanol vapor for 4 hr. The ADH-positive strain exhibited up to a 72% increase in the rate of ethanol elimination after exposure to ethanol vapor compared to the ethanol-injected controls. In contrast, treatment with ethanol vapor did not alter rates of ethanol elimination in the ADH-negative strain. These data demonstrate clearly that ADH is required for SIAM in the deer mouse. In addition, in both the ADH-positive and the ADH-negative strain, rates of ethanol elimination increased in both the ethanol-injected and vapor-treated groups 2- to 3-fold as the dose of ethanol was increased from 100 to 500 mg/100 ml. Thus, it is concluded that this "concentration effect" of ethanol on rates of ethanol metabolism does not involve ADH in the . deer mouse.     

The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury

The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFalpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis.     

Effects of cysteine on the pharmacokinetics of intravenous phenytoin in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigated after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities were significantly smaller (164, 103 and 95.3 pmol/min per mg protein for the control rats, and rats with PCM and PCMC, respectively) than that in control rats. In rats with PCMC, the intrinsic clearance of phenytoin, CL(int) was significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pHPPH could be reduced in rats with PCM and PCMC. This was supported by significantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) in rats with PCM and PCMC than that in control rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 microg/min), apparent volume of distribution in central compartment (44.4, 65.4 and 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-time curve from time zero to time infinity (609, 714 and 1210 microg min/ml), renal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excretion (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were not returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activity in rats with PCMC was not returned to control level.