Relationship between the severity of experimental diabetes and altered lung phospholipid metabolism

Glucose intolerance was induced in rats by iv infusion of streptozotocin (STZ) in doses of 30, 40, 50, and 100 mg/kg. Serum glucose concentrations were elevated versus controls and weight gains were reduced in a dose-dependent fashion up to 50 mg/kg. Urine outputs and blood urea nitrogen (BUN) values were higher than control values in the animals treated with 40 and 50 mg/kg and serum albumin concentrations were decreased after infusion with 50 mg STZ/kg. Lung phosphatidylcholine (PC) concentrations and dry-to-wet weight ratios were unchanged by STZ treatment, while lung protein and disaturated phosphatidylcholine (DSPC) concentrations were depressed in the 50-mg/kg group. Animals surviving treatment with 100 mg/kg demonstrated increased fasting blood glucose levels, BUN values, and 48-hr urine outputs, and decreased lung protein levels. However, these alterations were less than those found in the 50-mg/kg animals. Pulmonary concentrations of PC, DSPC, and lung dry-to-wet weight ratios were unchanged. It was found advantageous to express the results relative to fasting blood glucose levels. This demonstrated that urine output and BUN values increased and weight gain decreased with rising glucose concentrations, but serum albumin decreased only in moderate and severe hyperglycemia. Fasting glucose concentrations greater than 400 mg/dl were associated with reduced lung DSPC and protein levels, while pulmonary PC and dry-to-wet weight ratios demonstrated no change with increasing hyperglycemia.     

Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.     

Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Studies of embryo-fetal development in rats were conducted with two 5-lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 500 mg/kg/day) was administered orally by gavage to female rats on days 6-17 postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100 mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and 21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661 (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB-202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body weight by 15-30% and produced extensive cardiovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary septation, the aortic arch, pulmonary trunk, and ventricular septal defects are discussed relative to comparable human syndromes of cardiovascular malformation.     

Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats

The aim of this study was to investigate the effects of Ginkgo biloba extract (EGb 761) on male copulatory behavior in rats. EGb 761 (1 mg/ml) induced significant production of testosterone (T) in rat Leydig cells in vitro. Its effects on sexual behavior were then tested in Long-Evans male rats after 7, 14, 21, or 28 days of oral gavage of vehicle (distilled water) or EGb 761 at doses of 10, 50, or 100 mg/kg. Administration of 50 mg/kg of EGb 761 for 28 days and of 100 mg/kg for 14 or 21 days significantly increased intromission frequency compared to controls on the same day. An increase in ejaculation frequency was seen after treatment with 50 mg/kg of EGb 761 for 14, 21, or 28 days when compared to either the control group on the same day or the same group on day 0. A reduction in ejaculation latency was only seen after administration of 50 mg/kg of EGb 761 for 14 days compared to the vehicle-treated group. After treatment for 28 days, no significant difference was seen in mount latency, intromission latency, serum T levels, reproductive organ weight, sperm number, or levels of the metabolite of dopamine, 3,4-dihydroxyphenylacetic acid in the brain with any dose of EGb 761, but significantly reduced serum prolactin levels and increased dopamine levels in the medial preoptic area and arcuate nucleus were seen at the dose of 50 mg/kg. These findings show that EGb 761 (especially at the dose of 50 mg/kg) enhances the copulatory behavior of male rats and suggest that the dopaminergic system, which regulates prolactin secretion, may be involved in the facilitatory effect of EGb 761.     

Developmental toxicity of temafloxacin hydrochloride in the long-tailed macaque (Macaca fascicularis)

The potential developmental toxicity of temafloxacin hydrochloride was studied in the long-tailed macaque (Macaca fascicularis). Ten animals in each of the three drug-treated groups (25, 50, and 100 mg/kg) were administered temafloxacin via nasogastric intubation during gestational days (GD) 20-50. A control group of ten animals received vehicle only. The dams were monitored daily for adverse physical signs and maternal blood samples were collected for analyses of serum progesterone (P), 17 beta-estradiol (E2), and chorionic gonadotropin (CG). In addition, the conceptus was monitored periodically by ultrasound during gestation to confirm growth and viability. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality were observed at 100 mg/kg, and a no-observable-adverse-effect-level (NOAEL) of 50 mg/kg was established. The incidence of prenatal mortality was as follows: Control = 1/10 (10%); 25 mg/kg = 1/10 (10%); 50 mg/kg = 2/10 (20%); and 100 mg/kg = 5/10 (50%). Analysis of P, E2, and CG indicated no significant effect of treatment. In addition, no significant differences were observed in embryonic/fetal growth and development when compared to historical controls. No gross structural changes were observed in fetuses exposed to 50 or 100 mg/kg, although one fetus exposed to 25 mg/kg exhibited microphthalmia. This anomaly was considered spontaneous and, therefore, unrelated to treatment.     

Teratogenic effect of trifluoperazine in rats and mice

Trifluoperazine was administered to pregnant mice and rats by gastric intubation during the period of organogenesis. Dams were treated at doses of 0.5, 5, 50 (mice and rats) and 100 (only rats) mg/kg/day. The drug affected the pregnant weight increment in a dose-related manner in rats but only the 50 mg/kg/day dose level affected the weight gain of mice. The foetal weight was not markedly affected in either species. The drug induced cleft palate and micrognathia in rats but did not produce a teratogenic effect in mice. Trifluoperazine caused abortions in mice and there were significant increases in the number of resorptions with the top dose levels in both species.     

Abortifacient principle of Achyranthes aspera Linn

Achyranthes apsera is an abundant indigenous herb in India. Extracts of the whole plant had shown an abortifacient effect in mice. Maximal activity was in the benzene extract which was tested. The drug, in olive oil, was given orally to rabbits in doses of 50 mg/kg of body weight on the 8th day postcoitum. Laparotomy was done on the 11th day. No implantation sites were found. However, ovaries contained prominent corpus luteum, indicating that the drug had prevented pregnancy. In rats, the drug was given orally as a single dose of 50 mg/kg of body weight on the 6th or 7th day after mating. No effect was observed. In mice the drug was given at a single dose of either 10, 15, 25, or 50 mg/kg of body weight. For toxicity tests in mice, a single dose of 1000 mg/kg of body weight was given. After 1 month animals were autopsied and the organs examined. The drug was nontoxic. For a chronic toxicity test 75 mg/kg of body weight was given every 21 days. After 6 months of drug treatment, blood and tissue samples were examined. No toxic effects were observed. For a teratogenic study, 15 mated female mice were fed 10 or 25 mg/kg of body weight on Day 6 of gestation. 3 generations of offspring showed no malformations. In mice, abortifacient effects were noted with a maximum activity at 50 mg/kg of body weight. The drug showed no estrogenic, antiestrogenic, or androgenic effects in mice. Progesterone or pituitary extract given along with the drug did not prevent abortions in mice. The drug was species-specific in that no abortifacient effect was found in rats.     

TGF‐β1 monoclonal antibody: Assessment of embryo‐fetal toxicity in rats and rabbits

A humanized monoclonal antibody targeting transforming growth factor β1 (TGF‐β1 mab) has been used in development for the treatment of chronic kidney disease. Embryo‐fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF‐β1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18. Maternal reproductive endpoints and fetal viability, weight, and morphology were evaluated. There was no indication of maternal or embryo‐fetal toxicity in the rat. Effects in the rabbit were limited to the fetus where the 30 mg/kg TGF‐β1 mab dose produced a slight decrease in fetal weight and an increase in the incidence of retrocaval ureter and an absent and/or malpositioned kidney/ureter in two fetuses. In conclusion, TGF‐β1 mab produced no adverse maternal or embryo‐fetal findings in rats when administered ≤50 mg/kg on GDs 6, 10, and 14. TGF‐β1 mab did not demonstrate maternal toxicity or embryo‐fetal lethality at doses as high as 30 mg/kg when administered on GDs 7, 12, 14, 16, and 18 in rabbits. Fetal growth and morphology were affected only at 30 mg/kg; thus, the no observed adverse effect level was 3 mg/kg in rabbits. The margin of safety for both rats and rabbits was ≥37‐fold the clinical exposure level.     

The effect of caffeine in the in vivo SCE and micronucleus mutagenicity tests

Caffeine which was administered per os to outbred mice either twice, 30 and 6 h before sacrifice or once, 30 h before sacrifice, at dose levels of 50, 75 or 100 mg/kg body weight only caused a weak induction of micronuclei at the highest dose. Again a level of 100 mg caffeine per kg body weight was required before a weak but not significant effect could be observed in the micronucleus test using a mutagen-sensitive inbred strain of mice. In Chinese hamsters caffeine doses of 45, 75, 150 or 300 mg/kg body weight either given once or twice per os at the same time schedule as used for the mice also caused a clear cut induction of micronuclei only at the highest dose level. In the SCE test with Chinese hamster again 300 mg of caffeine were necessary to obtain a mutagenic effect although this test is considered to be more sensitive to mutagenic damage than the micronucleus test. It can therefore be concluded that caffeine causes DNA damage only at dose levels in the LD50 range which is higher for hamsters than for mice.     

Results of the negative control chemical allyl alcohol in the 15-day intact adult male rat screening assay for endocrine activity

Development, standardization, and validation of methods to assess the potential of chemicals to disrupt hormonal homeostasis have been the focus of considerable research efforts over the past 10 years. As part of our validation effort, we evaluated the specificity of the 15-day intact adult male rat assay, using a negative control chemical, allyl alcohol, a known hepatotoxicant that was not expected to induce endocrine effects. Male rats were dosed for 15 days via oral gavage with 0, 10, 30, 40, or 50 mg/kg/day allyl alcohol. The endpoints evaluated included final body and organ weights, serum hormone concentrations, and a limited histopathology assessment. No mortality or adverse clinical signs were observed. Mean final body weight for rats in the 50-mg/kg/day dose group was decreased to 90% of control. Mean relative liver weights were increased at 40 and 50 mg/kg/day (115% and 117% of control, respectively). Serum testosterone and DHT concentrations were statistically significantly decreased at 50 mg/kg/day (72% of control). Serum prolactin concentrations were statistically significantly decreased at 40 mg/kg/day (58% of control), but not at 50 mg/kg/day. There were no effects on the other endpoints evaluated. Consistent with previous guidance for interpreting the 15-day intact adult male rat assay, histological and weight changes of target organs were given a higher weight-of-evidence than changes in serum hormone concentrations alone. Therefore, with only minimal changes in serum hormone concentrations and no effects on organ weights or microscopic alterations, the results of allyl alcohol in the 15-day intact adult male rat assay were considered negative and consistent with the predicted results.     

Developmental toxicity evaluation of Bendectin in CD rats

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed-pregnant CD rats (36-41/group) during organogenesis (gestational days [gd] 6-15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).     

Effect of WR-2721 on fetal development in the rat

The radioprotector WR-2721 has been shown to radioprotect all tissues studied except the central nervous system. However, it has not yet been used to radioprotect the fetus. In this study we determined that [14C]WR-2721 injected into pregnant rats quickly passed the placenta and was concentrated by the fetus. In addition, we evaluated the toxicity of WR-2721 (2.5-600 mg/kg) to pregnant rats and their fetuses during the period of major organogenesis at Days 9, 11, and 14 postconception. Pregnant animals were only slightly more (10%) sensitive (LD50, 580 mg/kg) to WR-2721 than nonpregnant cohort animals (LD50, 640 mg/kg). At concentrations of 50 mg/kg or less there was a small but statistically significant increase in fetal deaths, while at doses greater than 300 mg/kg a larger degree of fetal mortality occurred. Maximal fetal weight loss, to about 84% of control, was found at 500 mg/kg. No changes in head dimensions or gross malformations of the surviving fetuses were detected at any time or concentration. Of all the parameters measured in this study none demonstrated a predilection for any specific period of major organogenesis. The results of this study indicate that while WR-2721 demonstrates a dose-related embryotoxicity it is not teratogenic.     

Antihypertensive effect of an extract of Passiflora edulis rind in spontaneously hypertensive rats

Orally administered methanol extract of Passiflora edulis rind (10 mg/kg or 50 mg/kg) or luteolin (50 mg/kg), which is one of consistent polyphenols of the extract, significantly lowered systolic blood pressure in spontaneously hypertensive rats (SHRs). Quantitative analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) showed that the extract contained 20 microg/g dry weight of luteolin and 41 microg/g dry weight of luteolin-6-C-glucoside. It also contained gamma-aminobutyric acid (GABA, 2.4 mg/g dry weight by LC-MS/MS or 4.4 mg/g dry weight by amino acid analysis) which has been reported to be an antihypertensive material. Since the extract contained a relatively high concentration of GABA, the antihypertensive effect of the extract in SHRs might be due mostly to the GABA-induced antihypertensive effect and partially to the vasodilatory effect of polyphenols including luteolin.     

Effect of aqueous leaf extract of Azadirachta indica on the reproductive organs in male mice

Effect of oral administration (50, 100, and 200 mg/kg body weight/day, for 28 days) of aqucous leaf extract of neem (Azadirachta indica) on the male reproductive organs of the Parkes (P) strain mice was investigated. The treatment had no effect on body weight and the reproductive organs weight. In treated mice, testes showed both normal and affected seminiferous tubules in the same sections; the affected seminiferous tubules showed intraepithelial vacuolation, loosening of germinal epithelium, marginal condensation of chromatin in round spermatids, occurrence of giant cells, mixing of germ cell types in stages of spermatogenesis and degenerated appearance of germ cells. In severe cases, the tubules were lined with Sertoli cells only, Sertoli cells and rare germ cells, or with Sertoli cells and several germ cells but without cellular association patterns. Also, the frequency of affected seminiferous tubules in testes of the extract-treated mice was significantly higher than the controls, though this remained unaffected in mice treated at 50 mg/kg body weight of the extract. Doses at 50 or 100 mg/kg body weight of neem leaf extract did not cause appreciable alterations in histological appearance of the epididymis, while a dose of 200 mg/kg body weight caused marked alterations both in histological appearance and the level of sialic acid in the duct. The treatment also had adverse effects on motility, morphology, and number of spermatozoa in the cauda epididymidis, level of fructose in the seminal vesicle, and on litter size. After 42 days of withdrawal of the treatment, the alterations induced in the reproductive organs recovered to control levels. Our results suggested that treatment with neem leaf extract caused reversible alterations in the male reproductive organs of P mice.     

Genotoxicity of 2-[2-(acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and 4-amino-3,3'-dichloro-5,4'-dinitro-biphenyl (ADDB) in goldfish (Carassius auratus) using the micronucleus test and the comet assay

2-[2-(Acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and 4-amino-3,3'-dichloro-5,4'-dinitrobiphenyl (ADDB) are two compounds, which show strong mutagenicity toward bacteria, that have been identified as major mutagens in river water in Japan. In the present study, we examined the genotoxicity of PBTA-6 and ADDB in goldfish (Carassius auratus) by the micronucleus test and single-cell gel electrophoresis (comet assay). The frequencies of micronuclei in gill cells gradually increased until 96h after i.p. injection of PBTA-6 and ADDB at doses of 50mg/kg body weight, and then decreased 144h after injection. PBTA-6 induced micronuclei in gill cells dose-dependently at a dose range of 1-100mg/kg body weight, giving significantly high frequencies at doses of 50 and 100mg/kg body weight. On the other hand, no significant increase was observed in the peripheral erythrocytes of goldfish exposed to PBTA-6 or ADDB. In the comet assay, values of DNA tail moment and tail length in peripheral erythrocytes increased significantly until 6h after the i.p. injection of PBTA-6 (50mg/kg body weight), only to decrease by 9h after injection. Both the DNA tail moment and tail length were dose-dependently increased by injections of PBTA-6 at doses ranging from 1 to 50mg/kg. Significantly high values for tail moment and tail length were found in peripheral erythrocytes 3h after an i.p. injection of ADDB and persisted for up to 6h. These results show that both PBTA-6 and ADDB have genotoxic effects in goldfish.     

Postnatal development of rat pups after maternal exposure to diethanolamine

BACKGROUND: Diethanolamine (DEA), a widely used surfactant, was administered to pregnant mice at the oral LD10 resulting in failure of pups to grow and thrive through postnatal day (PND) 3 [National Toxicology Program, 1987; York et al., Teratology 37:503-504, 1988]. The toxicity profile for DEA differs among rodent species. This study investigated DEA-induced postnatal toxicity in a second species. METHODS: Timed-mated Sprague-Dawley rats were dosed (0, 50, 125, 200, 250, or 300 mg DEA/kg/day, p.o.) on gestational days (GD) 6-19. Dams and pups were monitored for body weight, feed/water intake, clinical signs, litter size, and sex ratio. At necropsy (PND 21), maternal liver and kidney weights and number of uterine implantation sites were recorded. RESULTS: The high-dose group was terminated early due to excessive toxicity. The estimated maternal LD10 was 218 mg/kg/day. Maternal effects included decreased body weight and relative feed intake (>or=200 mg/kg/day), transiently reduced relative water intake (125 and 250 mg/kg/day), and increased absolute kidney weight (>or=125 mg/kg/day). Postimplantation loss (PND 0) and pup mortality (PND 0-4) were increased (>or=200 and >or=125 mg/kg/day, respectively). Pup body weight was reduced (>or=200 mg/kg/day) as late as PND 21. CONCLUSIONS: This study demonstrates reduced postnatal growth and survival in a second species after gestational exposure to DEA, persistence of toxic effects through the end of lactation, possibly due to long elimination half-life, and maternal and developmental toxicity no-observed-adverse-effect level (NOAELs) (50 mg/kg/day) and lowest-observed-adverse-effect level (LOAELs) (125 mg/kg/day) for oral DEA exposure during embryo/fetal development in the rat.     

Effects of the Ay gene on susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice

Effects of the Ay gene, a coat color gene, on susceptibility to hydrocortisone fetotoxicity and teratogenicity were investigated by using the congenic strain of C57BL/6-Ay (Ay/a) which had been maintained by repeated back-crosses of the Ay gene to the C57BL/6 (a/a) background. Matings were conducted as follows (female x male): group I, a/a; group II, a/a x Ay/a; and group III, Ay/a x a/a. Pregnant females were subcutaneously given daily doses of 0, 12.5, 25, or 50 mg/kg of hydrocortisone on days 10-13 of pregnancy. On day 18 of pregnancy, fetuses were sexed, weighed, and examined for external abnormalities. In group I, the mean fetal weight was significantly decreased at a dose of 25 mg/kg or more. The incidences of cleft palate were 3.2 and 22.7% at 25 and 50 mg/kg, respectively. In group II, in which half of the fetuses were expected to carry the Ay gene, the mean fetal weight was decreased significantly at 12.5 mg/kg or more. The incidence of cleft palate in group II at 50 mg/kg was 44.2%, which was significantly higher than that in group I. In group III, in which maternal mice as well as half of their fetuses carried the Ay gene, a decrease in the mean fetal weight was greater than in group II. In addition, the mean percentage of fetal resorptions was significantly increased at 50 mg/kg. The incidence of cleft palate in group III was significantly increased at 25 mg/kg (10.5%) when compared with those in groups I and II. These results indicate that the Ay gene may be associated with susceptibility to hydrocortisone fetotoxicity and teratogenicity in mice.     

VE和L-肌肽对大菱鲆幼鱼生长、抗氧化、非特异性免疫及血清生化指标的影响

实验以大菱鲆（Scophthalmus maximus）幼鱼[（14.00±0.02）g]为研究对象,采用2×4双因素设计,设2个VE水平（0和75 mg/kg）和4个L-肌肽水平（0、50、100和200 mg/kg）,研究VE和L-肌肽对其生长、抗氧化、非特异性免疫及血清生化指标的影响。实验共分8组,每组3个重复,每个重复46尾鱼,实验周期为8周。结果显示:（1）在饲料中添加75 mg/kg VE显著提高了大菱鲆幼鱼增重率（WGR）和特定生长率（SGR）（P < 0.05）,L-肌肽添加量≤100 mg/kg对实验鱼生长性能无显著影响（P>0.05）,添加量为200 mg/kg时鱼体WGR、SGR和蛋白质效率（PER）显著降低,饲料系数（FCR）显著升高（P < 0.05）;（2）VE和L-肌肽对血清谷胱甘肽过氧化物酶（GSH-PX）、过氧化氢酶（CAT）活性和丙二醛（MDA）含量及肝脏总抗氧化能力（T-AOC）、超氧化物歧化酶（SOD）活性和MDA含量均具有显著的交互作用（P < 0.05）,在VE 75 mg/kg水平下,L-肌肽添加量为50和100 mg/kg时血清GSH-PX活性最高,L-肌肽添加量为100和200 mg/kg时血清CAT活性最高且与添加量为50 mg/kg差异不显著（P>0.05）,添加100 mg/kg肝脏T-AOC和SOD活性达到最高且50 mg/kg组的SOD与100 mg/kg组差异不显著（P>0.05）,主效应结果显示,VE显著提高了血清T-AOC、SOD及肝脏CAT活性（P < 0.05）,L-肌肽显著提高了血清T-AOC（P < 0.05）;（3）VE和L-肌肽对血清补体C3和LZM活性交互作用显著,在75 mg/kg VE水平下,L-肌肽添加量为50 mg/kg时,补体C3水平最高（P < 0.05）,主效应显示,VE和L-肌肽对血清总蛋白（TP）影响均不显著（P>0.05）;（4）添加VE显著降低了血清总胆固醇（TCHO）和甘油三酯（TG）含量（P < 0.05）,添加L-肌肽显著降低了血清TG含量,且在L-肌肽50 mg/kg时达到最低。综合考虑大菱鲆幼鱼[（14.00-39.43）g]的生长性能、抗氧化性能、非特异性免疫及血清生化指标得出,在实验配方条件下（鱼油70 g/kg,大豆卵磷脂10 g/kg）,添加VE 75 mg/kg时,L-肌肽的适宜添加量为50 mg/kg。     

Induction of rat hepatic drug metabolizing enzymes by dimethylcyclosiloxanes

Low molecular weight dimethylcyclosiloxanes (DMCS) are important precursors in the synthesis of polydimethysiloxane polymers widely used in industry, and in medical and personal care products. The objective of this study was to characterize the ability of two DMCS, octamethylcyclosiloxane (D4) and decamethylcyclopentasiloxane (D5) to induce drug metabolizing enzymes in rats. Male and female Sprague-Dawley rats were administered 1, 5, 20, or 100 mg/kg D4 or D5 in corn oil daily by gavage for 4 days. Changes in the levels of activity and/or immunoreactivity of CYP1A1/2, CYP2B1/2, CYP3A1/2 and NADPH cytochrome P450 reductase in liver microsomes were examined. Significant increases were observed in the liver to body weight ratio in female rats administered either D4 or D5 at doses > or = 20 mg/kg. Increases in the liver to body weight ratio were observed in male rats treated with > or = 100 mg/kg D5 but not with D4. Relatively large increases in CYP2B1/2 enzymatic activity and immunoreactive protein were observed with increasing concentrations of both D4 and D5. Significant increases in 7-pentoxyresorufin O-depentylase (PROD) activity were also detected in male and female rats given D4 at doses > or = 5 mg/kg. D5 increased PROD activity in male rats at doses > or = 20 mg/kg and in female rats at doses > or = 5 mg/kg. 7-Ethoxyresorufin O-deethylase (EROD) activity was increased in both male and female rats receiving > or = 20 mg/kg D4 or > or = 5 mg/kg D5; however, no changes were detected in CYP1A1/2 immunoreactive protein in rats of either sex. D4 and D5 caused significant increases in CYP3A1/2 immunoreactive protein in only male rats treated with 100 mg/kg of either compound. However, significant increases were detected in CYP3A1/2 immunoreactive protein in female rats at D4 doses > or = 20 mg/kg and D5 doses > or = 5 mg/kg. Induction of NADPH cytochrome P-450 reductase immunoreactive protein was observed with D4 in female rats and in both male and female rats with D5. Induction of CYP2B/1/2, CYP3A1/2 and NADPH cytochrome P450 reductase was observed in rats treated with 50 mg/kg phenobarbital by intraperitoneal injection. Maximal CYP2B induction detected with D4 was approximately 50% of the increase observed with phenobarbital. In summary, D4 and D5 induced CYP2B1/2 in adult rat liver in a manner similar to that observed with phenobarbital; however, differences were observed between D4 and D5 in their ability to induce CYP3A1/2 and NADPH cytochrome P450 reductase. Female rats were more sensitive to the inductive properties of low doses of both DMCS than male rats whereas male rats were more responsive to phenobarbital induction.