共查询到20条相似文献,搜索用时 15 毫秒
1.
C Ioannides S L Bass A D Ayrton J Trinick R Walker P R Flatt 《Chemico-biological interactions》1988,68(3-4):189-202
The effect of chemically-induced diabetes on the hepatic microsomal mixed-function oxidase system and the activation of chemical carcinogens was investigated in animals treated with streptozotocin (STZ). In order to distinguish between the effects of the diabetogenic chemical per se and that of the diabetic state, groups of STZ-treated animals received either nicotinamide simultaneously with STZ to prevent the onset of diabetes, or daily treatment with insulin in order to reverse the effects of diabetes. STZ-treated animals exhibited higher pentoxyresorufin O-dealkylase, ethoxy-resorufin O-deethylase, ethoxycoumarin O-deethylase, aniline p-hydroxylase and NADPH-cytochrome c reductase activities; similarly, increases were seen in cytochrome P-450 and b5 levels. All of these effects were prevented by nicotinamide and, at least partly, antagonised by insulin therapy. Treatment of animals with STZ markedly increased the activation, by liver microsomes in vitro, of Trp-P-1 and Trp-P-2 to mutagens, the effect being totally preventable by nicotinamide and successfully antagonised with insulin therapy. The diabetic animals were similarly more efficient in activating MeIQ but the effect was not preventable by nicotinamide or reversed by insulin. In contrast no changes were seen in the activation of IQ and only a modest increase in the case of MeIQx. It is concluded that diabetes may modulate the metabolic activation of some chemical carcinogens, presumably by changing the ratio of the various cytochrome P-450 isoenzymes. 相似文献
2.
Cytochrome P-450 dependent hydroxylation of testosterone has been measured in hepatic microsomes of control, diabetic and insulin-treated diabetic rats. The observed decrease in testosterone 16 alpha-hydroxylase activity in diabetes, an activity previously shown to be largely due to RLM5, was accompanied by a dramatic decrease in immunodetectable RLM5. Diabetic rats which received insulin had elevated testosterone 16 alpha-hydroxylase activity relative to the diabetic animals, which was accompanied by a corresponding increase in the levels of RLM5. These results provide evidence that specific constitutive cytochrome P-450 enzymes are altered in the diabetic state and that these changes are not permanent since they can be overcome, at least partially, by insulin replacement therapy. 相似文献
3.
Feeding of vitamin A-deficient diet to male weanling rats for 10 weeks resulted in significant decrease in the body weight and marked reduction in the hepatic vitamin A content. The levels of hepatic phase I microsomal enzymes cytochrome P-450, cytochrome b5, aminopyrine N-demethylase and arylhydrocarbon hydroxylase were found to be substantially reduced by vitamin A-deficiency. Also, the activity of phase II microsomal UDP - glucuronyl transferase enzyme was significantly decreased in deficient animals. Following repeated oral administration of DDT (15 mg/kg/body wt/day) for 21 days, the phase I microsomal enzymes were induced to a greater extent in controls as compared to deficient animals. UDP - glucuronyltransferase remained insensitive to DDT induction. The results imply that the capacity for induction of the hepatic mixed-function oxidase enzyme system is impaired in deficient animals concurrently exposed to DDT. 相似文献
4.
The effect of intratracheal instillation of different doses of benzo(a)pyrene (0.1, 1.0 and 2.0 mg) on the drug metabolizing enzymes of lung and liver was analysed in rats fed diet with or without vitamin A for 5-6 weeks. Benzo(a)pyrene exposure at 2.0 mg dose only elevated the level of cytochrome P-450 and b5, and activity of benzopyrene hydroxylase in liver, and extent of increase was similar in normal and vitamin A deficient groups. Contrary to this, pulmonary contents of cytochrome P-450 and b5, and benzopyrene hydroxylase activity increased over control values in both the groups even at lower doses of benzo(a)pyrene. Moreover, their values were higher in vitamin A deficient-treated groups compared to normal-treated controls. Increase in these parameters was greater in lung as compared to increase in liver. NADPH cytochrome C-reductase in lung and liver was not affected either by inducing vitamin A deficiency or exposing these rats further to benzo(a)pyrene. Uridine-diphospho-glucuronosyl-transferase (UDP-GT) activity in normal and vitamin A deficient groups was enhanced following exposure to benzo(a)pyrene both in lung and liver. However, activity of this enzyme remained impaired in vitamin A deficient groups, benzo(a)pyrene exposed or not exposed when compared to respective normal controls. Glutathione S-transferase activity remained unchanged following exposure to benzo(a)pyrene both in lung and liver. The apparent increase in hepatic glutathione S-transferase and decrease in pulmonary glutathione S-transferase activity in vitamin A deficiency was only due to vitamin A deficient status of rats with no further effect of benzo(a)pyrene. 相似文献
5.
The administration of ethanol as 36% of the total calories in a nutritionally adequate liquid diet for three weeks to male Wistar rats caused a 36% decrease in hepatic vitamin A levels (P less than 0.001) when compared with glucose pair-fed control rats, without affecting serum levels of the vitamin. Simultaneous administration of a synthetic antioxidant, DPPD (N,N'-diphenyl-p-phenylene-diamine) to ethanol-fed rats caused a 73% decrease in the extent of the ethanol induced hepatic vitamin A depletion (P less than 0.001). DPPD administration did not affect weight gain, dietary (and hence ethanol) intake or serum ethanol and vitamin A levels in ethanol-fed rats, nor did it affect hepatic or serum vitamin A levels in pair-fed controls. Increased hepatic catabolism of retinoic acid due to induction of cytochrome P450 by ethanol has been suggested as a mechanism of depletion. In the current study, DPPD administration to ethanol-fed rats did not reverse the ethanol induced increase in microsomal cytochrome P450 concentrations or aniline hydroxylase activity. These findings indicate that the ethanol induced hepatic vitamin A depletion can be largely dissociated from the induction of cytochrome P450. In view of the potent free radical scavenging activity of vitamin A, and the protective effect of DPPD against ethanol induced hepatic loss of the vitamin, this study suggests that increased free radical generation and direct peroxidation of vitamin A may be an important mechanism by which ethanol induced hepatic vitamin A depletion occurs in the rat. 相似文献
6.
The effect of vitamin A deficiency on the drug-metabolizing enzyme system of the lung and liver was analyzed in rats fed diets with or without vitamin A for 5-6 weeks. The hepatic level of vitamin A was significantly reduced in vitamin A deficient animals. The hepatic cytochrome P-450 and b5 contents and activity of benzo(a)pyrene hydroxylase was significantly reduced in deficient animals. Contrary to this, pulmonary cytochrome P-450 and b5 contents were above the control values. No alteration in pulmonary benzo(a)pyrene hydroxylase was noted. The uridine diphosphate-glucuronosyltransferase activity of digitonin-treated microsomal membranes was below the control values both in lung and liver. However, the native uridine diphosphate-glucuronosyltransferase activity remained unchanged in the liver and was below control values in the lung. 相似文献
7.
We investigated whether dietary supplementation with L-arginine, the endogenous precursor of nitric oxide, might affect serum lipid levels and activities of intestinal mucosa enzymes in animals, in which diabetes was induced by administration of streptozotocin. Control and diabetic rats were fed diets with or without 2% L-arginine supplementation for 4 weeks. Diabetic rats had significantly higher concentrations of serum triglycerides and LDL-cholesterol than control rats. These alterations were partially reduced by L-arginine supplementation. Experimental diabetes did not influence the lactase and leucine aminopeptidase activity in the intestine, but the activity of alkaline phosphatase was increased. Furthermore, activities of maltase and sucrase in the intestinal mucosa were elevated in streptozotocin-induced diabetic rats and were restored to control levels after dietary L-arginine supplementation. On the basis of the present experimental evidence, dietary L-arginine supplementation appears to affect the metabolism of lipoproteins and might alleviate some gastrointestinal dysfunctions, commonly seen in diabetes mellitus. 相似文献
8.
N-Nitrosocarbaryl (N-methyl-1-naphthyl N-nitrosocarbamate) was intraperitoneally administered to male and female rats on four consecutive days at the following doses: 6.25 mg, 12.5 mg, 25 mg and 50 mg/kg body weight/day in olive oil solution; the controls received just the oil. In a second experiment, a daily intraperitoneal dose of 25 mg/kg of N-nitrosocarbaryl was given for 1, 2, 3 or 4 days; the animals were killed 24 h after the last treatment. The two following microsomal enzymatic activities were assayed: aniline aromatic hydroxylase and p-nitroanisole O-demethylase; the levels of cytochrome P-450, proteins and RNA were measured in the hepatic microsomal fraction. N-Nitrosocarbaryl is an inhibitor of the two investigated microsomal monooxygenases at doses of 25 and 50 mg/kg when administered on 4 consecutive days. During the daily administration, enzyme inhibition is seen in females after one day of treatment whereas cytochrome P-450 only becomes lowered after 4 days of administration. In males, no modification of this parameter is observed whereas the activities of microsomal monooxygenases are inhibited. These results suggest that N-nitrosocarbaryl could act on the active sites of the enzymes which metabolize aniline and p-nitroanisole. 相似文献
9.
We evaluated the tail-skin temperature response to administration of several doses of isoproterenol in streptozotocin-induced diabetic rats after 48 h and after 4 weeks of diabetes. Blood glucose concentrations were significantly increased over controls 48 hours after administration of streptozotocin (65 mg/kg, i.v.) and remained elevated to a similar degree in the 4-week group. Basal rectal temperature and tail-skin temperature (TST) were not different between controls and the diabetic groups and were not affected by administration of saline. However, administration of isoproterenol (25 micrograms/kg, s.c.) caused a significant rise in TST in the control group, but not in the rats diabetic for 4 weeks. A similar but exaggerated response was observed in the controls after subcutaneous administration of 40 micrograms/kg and 100 micrograms/kg of isoproterenol. The TST response in the 4-week diabetic rats still remained negligible with the two higher doses of isoproterenol. When the data were summarized as area under the TST curve, a dose-dependent increase was observed in the control groups and a significant absence of response was observed in the 4-week group. The rats studied 48 h after streptozotocin injection had a similar TST response to the control group after administration of 40 micrograms/kg of isoproterenol. Colonic temperatures did not significantly change between the two groups in any of the studies, although the colonic temperatures tended to rise in the control groups following administration of isoproterenol. We conclude from this study that the absence of a tail-skin temperature response in rats diabetic for 4 weeks results from either a reduced beta-adrenergic receptor mediated response or an altered neural thermoregulatory reflex response, or both. These changes are probably not due to streptozotocin treatment or increases in blood glucose. 相似文献
10.
Alterations of the aryl hydrocarbon hydroxylase system during riboflavin depletion and repletion 总被引:1,自引:0,他引:1
C S Yang 《Archives of biochemistry and biophysics》1974,160(2):623-630
The alterations of the microsomal aryl hydrocarbon hydroxylase system in mice during riboflavin depletion and repletion have been examined. During the development of riboflavin deficiency, there was a decrease in the activity of the flavoprotein NADPH-cytochrome c reductase accompanied by an increase in cytochrome P-450 concentration. The aryl hydroxylase activities of the deficient animals were only slightly lower than the controls when isolated microsomes were used for the assay and the extent of decrease was more pronounced when liver homogenates were used for the assay. Upon repletion of flavin to the deficient mice, there were sharp rises in both the NADPH-cytochrome c reductase and aryl hydroxylase activities and a moderate decrease in cytochrome P-450 concentration in the first 2 days. The aryl hydroxylase activity of the microsomes of deficient mice can be elevated by preincubating with FAD or FMN, suggesting that the flavin coenzyme and hence the holo-reductase is rate limiting for the overall hydroxylation. During the recovery from riboflavin deficiency, the aryl hydroxylase can be induced by 3-methylcholanthrene to a greater extent than with the controls. The implications of these observations are discussed. 相似文献
11.
1. The stimulated levels of phenylanine hydroxylase activity in liver extracts from streptozotocin-induced diabetic rats (Donlon and Beirne, 1982) have been correlated with an increased rate of phenylalanine catabolism in vivo. 2. The levels of hepatic phenylalanine hydroxylase protein in diabetic rats become elevated. This effect is not seen in diabetic animals concurrently treated with insulin. 3. The rate of synthesis of liver phenylalanine hydroxylase in 5-day diabetics is 260% that of control animals. 4. These observations are discussed with reference to the regulation of hepatic phenylalanine hydroxylase and phenylanine metabolism in rats. 相似文献
12.
Cytochrome P450 in livers of diabetic rats: regulation by growth hormone and insulin 总被引:3,自引:0,他引:3
Y Yamazoe N Murayama M Shimada K Yamauchi R Kato 《Archives of biochemistry and biophysics》1989,268(2):567-575
The effects of pituitary and pancreatic hormones on the change in hepatic cytochrome P450s were studied in alloxan- or streptozotocin-induced male rats. In two major sex-specific forms, P450-male and P450(6 beta-1), the former was decreased in chronic (5 week) diabetes to only less than one-third of controls and the latter was also reduced in early (1 week) diabetes. In contrast, a main phenobarbital-inducible form, P450b, was enhanced 25- to 30-fold in these diabetic rats. 3-Methylcholanthrene-inducible P448H was also elevated 3-fold in alloxan-induced diabetes. These changes in hepatic contents of P450-male, P450-6 beta-1, and P450b, which are under the regulation of pituitary growth hormone, associated well with the reported results of time-dependent changes in growth hormone levels in diabetes (G.S. Tannenbaum (1981) Endocrinology 108, 76-82), suggesting that the change in growth hormone level is a factor responsible for alterations in hepatic cytochrome P450s. Normalizing effects of insulin on these forms were also studied. Treatment of diabetic rats with insulin reversed the decreased amounts of both P450-male protein and mRNA. Insulin also normalized hepatic contents of P450b, P4506 beta-1, and P448H. However, the treatment of hypophysectomized rats with insulin had no effect, and treatment of diabetic rats with growth hormone or a suppressing agent of somatostatin, cysteamine, showed trivial effects on P450-male and P450b. These results suggest that insulin does not act directly as a substitute of growth hormone, but exerts its effect indirectly through the normalization of a growth hormone-mediated process(es) in diabetic rats. 相似文献
13.
14.
Elaidic and linoleic acids were administered at doses of 40 and 200 mg/kg i.p. every second day for 4 weeks to rats fed a fat-free diet. The fatty acids had only a slight effect on the weight gain of the animals. The amount of microsomal protein was slightly decreased with the higher dose of linoleic acid. The higher dose level of both fatty acids decreased the microsomal phospholipid content. The relative amounts of microsomal phospholipid fatty acids were also altered due to fatty acid administration. The activity of microsomal NADPH cytochrome c reductase and microsomal cytochrome P-450 contents were decreased by the higher dose of linoleic acid. The hepatic aryl hydrocarbon hydroxylase and p-nitroanisole O-demethylase activities decreased in fatty acid-treated rats. The UDP-glucuronosyltransferase activity was also lowered after the fatty acid administration. The results suggest that fatty acid-induced changes in the activities of drug-metabolizing enzymes may be due to the microenvironmental changes of membrane-bound enzymes. 相似文献
15.
Combined treatment of male Syrian golden hamsters with the synthetic estrogen diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF) gives rise to a high incidence of hepatocellular carcinomas, whereas no such tumors are formed with DES alone nor with 7,8-BF alone. To determine whether alterations in DES metabolism may account for the observed hepatocarcinogenicity, we have studied the effect of pretreatment with 7,8-BF alone, DES alone and 7,8-BF plus DES on the levels of hepatic P-450 and cytochrome b5, on the activities of various P-450 isoenzymes and on microsomal DES metabolism. Hepatic P-450 content was significantly increased after pretreatment with 7,8-BF and decreased after DES, while combined pretreatment led to levels similar to those in untreated control animals. Hepatic cytochrome b5 was also elevated in 7,8-BF-treated hamsters; DES pretreatment had no effect, and combined pretreatment led to a slight increase. Four different substrates were used to probe P-450 isoenzyme activity. Aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin-O-deethylase (ECOD), 7-ethoxyresorufin-O-deethylase (EROD) and 7-pentoxyresorufin-O-dealkylase (PROD) were all elevated after 7,8-BF-pretreatment, while DES led to a decrease in these activities with the exception of AHH, where a transient increase which was observed after 8 and 20 weeks of pretreatment was back to control levels after 32 weeks. Combined pretreatment with 7,8-BF and DES led to an intermediate response (slight increase) with AHH, EROD and PROD, but not with ECOD, where a full induction comparable with that observed after 7,8-BF alone was elicited. In spite of the modulation of enzyme levels and activities observed after the various pretreatments, the metabolism of DES in microsomes from pretreated animals was virtually identical with that from controls. Therefore it is concluded that modulation of hepatic DES metabolism is not the reason for the observed hepatotumorigenicity; instead, it is speculated that 7,8-BF is the carcinogenic agent in this tumor model, and DES may act as a promotor. 相似文献
16.
Effects of vitamin E and selenium supplementation on aldehyde oxidase (AO) and xanthine oxidase (XO) activities and antioxidant status in liver, kidney, and heart of streptozotocin (STZ)-induced diabetic rats were examined. AO and XO activities increased significantly after induction of diabetes in rats. Following oral vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) intake once a day for 4 weeks, XO activity decreased significantly. AO activity decreased significantly in liver, but remained unchanged in kidney and heart of vitamin E- and selenium-treated rats compared to the diabetic rats. Total antioxidants status, paraoxonase-1 (PON1) and erythrocyte superoxide dismutase activities significantly decreased in the diabetic rats compared to the controls, while a higher fasting plasma glucose level was observed in the diabetic animals. The glutathione peroxidase activity remained statistically unchanged. Malondialdehyde and oxidized low-density lipoprotein levels were higher in the diabetic animals; however, these values were significantly reduced following vitamin E and selenium supplementation. In summary, both AO and XO activities increase in STZ-induced diabetic rats, and vitamin E and selenium supplementation can reduce these activities. The results also indicate that administration of vitamin E and selenium has hypolipidemic, hypoglycemic, and antioxidative effects. It decreases tissue damages in diabetic rats, too. 相似文献
17.
Immunoreactive somatostatin (IRS) was measured and characterized in plasma from the abdominal portel vein (PV) and inferior vena cava (IVC) of normal and streptozotocin diabetic rats. At 1 day following the induction of diabetes, PV and IVC levels of IRS were unchanged, at 2 weeks IVC IRS but not PV IRS was increased, but at 6 months both PV and IVC levels were strikingly elevated. Measurement of the IRS content of the pancreas and gut of the 6 month diabetic group showed a significant increase in the pancreas and stomach but not in the lower gut. Gel filtration of PV plasma from control and chronic diabetic rats revealed 3 immunoreactive forms with apparent m.w. of 12–15 K, 3.6 K and 1.6 K daltons. Immunoreactive somatostatin in the IVC was composed predominantly of the 12–15 K material in normal and diabetic rats. These results suggest that chronic but not acute streptozotocin diabetes leads to increased secretion of IRS from the pancreas and upper gut and to altered peripheral metabolism of IRS. Plasma IRS is heterogeneous, the main component being a high molecular weight form, the concentration of which is markedly increased in chronic insulinopenic diabetes. 相似文献
18.
Contents of hepatic microsomal protein, aminopyrine N-demethylase, acetanilide hydroxylase, aniline hydroxylase, hydrogen peroxide formation, cytochrome-c-reductase, cytochrome b5 and cytochrome P-450 were examined in control, phenobarbital (PB), 3-methylcholanthrene (3-MC) and 1, 1, 1-trichloro-2, 2-bis(p-chlorophenyl)ethane (DDT) treated group of 1-28 days old chickens. Increase in aminopyrine N-demethylase, acetanilide hydroxylase, aniline hydroxylase, cytochrome-c-reductase, cytochrome b5 and cytochrome P-450 was noticed at all stages of development during administration of PB and 3-MC. But these enzyme activities were not always paralleled by increase in age. Aminopyrine N-demethylase was increased in early stages only during DDT administration, which indicates that the form of cytochrome P-450, responsible for aminopyrine N-demethylation is present in early stages only. However, acetanilide hydroxylase was decreased in all stages of development, in postnatal development the basal activities of the enzymes for various substrates do not exhibit identical pattern, the degree of inducibility by inducers varied in relation to age of animal. Hydrogen peroxide formation increased in all stages of developing chickens due to the administration of PB and DDT. It however decreased due to 3-MC administration which may be due to induction of high spin cytochrome P-450. 相似文献
19.
Ewa Sewerynek Mitsushi Abe Russel J. Reiter Lornell R. Barlow-Walden Lidun Chen Timothy J. McCabe Linda J. Roman Beatriz Diaz-Lopez 《Journal of cellular biochemistry》1995,58(4):436-444
The protective effect of melatonin on lipopolysaccharide (LPS)-induced oxidative damage in phenobarbital-treated rats was measured using the following parameters: changes in total glutathione (tGSH) concentration, levels of oxidized glutathione (GSSG), the activity of the antioxidant enzyme glutathione peroxidase (GSH-PX) in both brain and liver, and the content of cytochrome P450 reductase in liver. Melatonin was injected intraperitoneally (ip, 4mg/kg BW) every hour for 4 h after LPS administration; control animals received 4 injections of diluent. LPS was given (ip, 4 mg/kg) 6 h before the animals were killed. Prior to the LPS injection, animals were pretreated with phenobarbital (PB), a stimulator of cytochrome P450 reductase, at a dose 80 mg/kg BW ip for 3 consecutive days. One group of animals received LPS together with Nw-nitro-L-arginine methyl ester (L-NAME), a blocker of nitric oxide synthase (NOS) (for 4 days given in drinking water at a concentration of 50 mM). In liver, PB, in all groups, increased significantly both the concentration of tGSH and the activity of GSH-PX. When the animals were injected with LPS the levels of tGSH and GSSG were significantly higher compared with other groups while melatonin and L-NAME significantly enhanced tGSH when compared with that in the LPS-treated rats. Melatonin alone reduced GSSG levels and enhanced the activity of GSH-PX in LPS-treated animals. Additionally, LPS diminished the content of cytochrome P450 reductase with this effect being largely prevented by L-NAME administration. Melatonin did not change the content of P450 either in PB- or LPS-treated animals. In brain, melatonin and L-NAME increased both tGSH levels and the activity of GSH-PX in LPS-treated animals. The results suggest that melatonin protects against LPS-induced oxidative toxicity in PB-treated animals in both liver and brain, and the findings are consistent with previously published observations related to the antioxidant activity of the pineal hormone. 相似文献
20.
Takatori A Akahori M Kawamura S Itagaki S Yoshikawa Y 《Journal of biochemical and molecular toxicology》2002,16(4):174-181
The effect of chronic hyperglycemia and hyperlipidemia induced by streptozotocin (SZ) on the expression of P450 in the liver of APA hamsters was studied in this experiment. No effect on the total activity of P450 was seen in SZ-induced diabetic hamsters throughout the experimental period. At 1 and 6 months after SZ-injection, the levels of CYP1A, 2C6, and 3A of SZ-injected hamsters were much lower than those of age-matched control hamsters. CYP2B expression tended to decrease and CYP2E1 and 4A expression tended to increase in SZ-injected hamsters, although the results were not significant. At 3 months after SZ-injection, however, no significant difference between SZ-injected and normal hamsters was seen in these P450 isozymes. On the other hand, CYP2C11 expression was slightly depressed in SZ1M and SZ6M, and almost equivalent to control hamsters in SZ3M. Immunohistochemistry by the use of each isozyme antibody revealed that SZ-induced diabetes affected the localization of CYP2C6, 3A, and 4A in the hepatic acinus. The expression of CYP2C6 and 3A was depressed mainly in the periportal region of the acinus, and CYP4A expression was induced mainly in the perivenous region by SZ-induced diabetes. On the other hand, the expression pattern of CYP1A, 2B, 2C11, and 2E1 were not affected. These results demonstrate that the effects of SZ-induced diabetes on hepatic P450 differ for each isozyme in APA hamsters and also differ from those of other experimental diabetic animals, including golden hamsters. 相似文献