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1.
H Jaeschke  A Wendel 《Toxicology》1985,36(1):77-85
Administration of either butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT) (1000 mg/kg/day for 5 days) to male mice increased the content of reduced glutathione by 50-100% in liver, lung, duodenum and intestine. In colon, glandular stomach, spleen and kidney no effect on glutathione level was observed. BHA and BHT led also to 100-1000% induction of glutathione transferases in liver, lung (only BHA), kidney and digestive tract (except the colon); the relative increase in transferase activity was greater with 1-chloro-2,4-dinitrobenzene (DCNB) as a substrate than with CDNB in all organs investigated. The effects of BHA, administered in olive oil by gavage, on different parts of the gastrointestinal tract revealed maximum increase of the glutathione content and transferase activities in the duodenum, smaller increase of these parameters in the upper intestine and no significant effects in the lower intestine and the colon. Starving mice for 1 day decreased the glutathione content of the liver by 50% to 21.3 +/- 4.5 nmol/mg protein in controls and to 39.4 +/- 3.3 in BHA-treated animals. Intravenous injection of 0.5 mmol GSH/kg restored the fed state (C: 37.4 +/- 2.8 nmol GSH/mg protein; BHA: 84.9 +/- 7.7) within 2 h. This indicates a much faster de novo synthesis of liver glutathione in BHA-pretreated animals. The mechanistic aspects of phenolic antioxidant effects on GSH metabolism are discussed.  相似文献   

2.
H Jaeschke  A Wendel 《Toxicology》1988,52(3):225-235
The mechanism by which high doses of the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) raise hepatic glutathione levels above physiological values was investigated in rats. A single dose of an antioxidant (200 mg/kg; p.o.) reduced the hepatic glutathione content by 17% (BHA) or 36% (BHT) after 5 h, but in contrast levels of 55% (BHA) or 34% (BHT) above controls (7.1 +/- 0.5 mumol GSH-equivalents/g liver wt) were measured 48 h after dosing. Both antioxidants increased basal bile flow (1.37 +/- 0.11 microliter/min per g liver wt) and biliary efflux of total glutathione, i.e. GSH and GSSG, (4.18 +/- 0.97 nmol GSH-eq./min per g) severalfold (up to 250%) over controls 24 h after in vivo antioxidant treatment. The sinusoidal efflux of reduced glutathione (14.9 +/- 2.2 nmol GSH-eq./min per g) was significantly reduced (BHA: 23%; BHT: 41%). The increased glutathione excretion into bile is likely to be independent of the induction of the choleresis. The secretion of bile salts was unaffected by BHA treatment and only temporarily reduced by BHT. Conclusion: phenolic antioxidants increase the hepatic turnover of glutathione by stimulating the biliary efflux of GSH. The resulting shift from a predominantly sinusoidal efflux of GSH in controls (hepato-renal circulation) to a predominantly biliary efflux of GSH in antioxidant-treated animals (entero-hepatic circulation) may lead to increased concentrations of cysteine, glycine and glutamic acid in the portal vein and consequently may stimulate the biosynthesis of GSH by enhanced substrate availability in the liver.  相似文献   

3.
The phenolic antioxidant butylated hydroxytoluene (BHT) is known to produce a dose-dependent increase in mouse lung weight which is characterized by the necrosis of pulmonary type I and endothelial cells. We studied the ability of butylated hydroxyanisole (BHA) to modify BHT-induced changes in lung weight in male CD-1 mice. BHA alone had no effect on lung weight up to a dose of 500 mg/kg (sc). However, when injected 30 minutes prior to sub-threshold doses of BHT (0-250 mg/kg, ip), BHA significantly enhanced lung weight in a dose-dependent manner. The ability of BHA to enhance BHT-induced changes in lung weight was dependent on both the time and the route of administration of BHA relative to BHT. Deuteration of BHT abolished the in vivo toxicity from the combination of BHA and BHT. These results suggest that the toxicity resulting from the combination of BHA and BHT is due to the formation of BHT-quinone methide and that the role of BHA might be either to deplete some protective mechanism in the target pulmonary cells or to enhance the biotransformation of BHT into BHT-quinone methide.  相似文献   

4.
The studies described in this report were designed to probe possible mechanisms whereby butylated hydroxyanisole (BHA) is able to enhance butylated hydroxytoluene (BHT)-induced mouse lung toxicity. In experiments with mouse lung slices, BHA enhanced the covalent binding of BHT to protein, indicating that the interaction between BHA and BHT takes place in the lung. Subcutaneous administration of either BHA (250 mg/kg) or diethyl maleate (DEM, 1 ml/kg) to male CD-1 mice produced a similar enhancement of BHT-induced lung toxicity. In contrast to DEM, the administration of BHA (250 or 1500 mg/kg) did not decrease mouse lung glutathione levels, suggesting that the effect of BHA is not due to the depletion of glutathione levels. We previously observed that in the presence of model peroxidases a unique interaction occurs between BHA and BHT, resulting in the increased metabolic activation of BHT. Upon the addition of hydrogen peroxide or various hydroperoxides to mouse lung microsomes, BHA significantly increased the covalent binding of BHT to protein. BHA also stimulated the rate of formation of hydrogen peroxide by 4.7-fold in mouse lung microsomes. Likewise, hydrogen peroxide resulting from the NADPH cytochrome P-450 (c) reductase-catalyzed redox cycling of tert-butylhydroquinone, a microsomal metabolite of BHA, supported the peroxidase-dependent BHA-enhanced formation of BHT-quinone methide. These results suggest that BHA could facilitate the activation of BHT in the lung as a result of both the increased formation of hydrogen peroxide and the subsequent peroxidase-dependent formation of BHT-quinone methide from the direct interaction of BHA with BHT.  相似文献   

5.
The kinetics and metabolism of butylated hydroxytoluene (BHT) in man and rats have been compared. Single oral doses of 200, 63 or 20 mg BHT/kg body weight were administered to rats and a single oral dose of 0.5 mg/kg body weight was ingested by human volunteers (non-smoking males). In rats, kinetic parameters (area under the plasma concentration-time curve, plasma BHT peak levels) showed a dose-dependent increase. Plasma BHT levels after oral administration were about four times higher than those that have been reported for another synthetic food antioxidant, butylated hydroxyanisole (BHA; Verhagen et al., Fd Chem. Toxic. 27, 151–158). This may be a reflection of a smaller volume of distribution for BHT, since there were no differences in plasma elimination half-life or plasma clearance between BHT and BHA. In man, the mean plasma concentration-time profile after oral BHT intake was well below the BHT profiles observed for rats and closely followed plasma BHA kinetics in man. In rats, the simultaneous administration of BHT (200 mg/kg body weight) and BHA (200 mg/kg) significantly decreased the absorption of BHT from the gastro-intestinal tract in the first few hours after treatment; the plasma kinetics of BHA were not influenced by the simultaneous administration of BHT. In human female volunteers no alterations in plasma BHT or BHA profiles were seen after the simultaneous ingestion of BHT (0.25 mg/kg body weight) and BHA (0.25 mg/kg). Rats excrete about 10% of an oral dose of 200 mg BHT/kg as unchanged BHT in the faeces, whereas in man no BHT could be detected in the faeces. Urinary excretion of (un)conjugated 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) accounts for only a small percentage of the administered dose in both rats and humans. It is concluded that the plasma BHT concentrations reached after the administration of a single medium to high dose of BHT to rats or a single low dose to man are very different.  相似文献   

6.
Aim of this study was to compare the effects of L-arginine (L-arg) and food-antioxidant butylated hydroxytoluene (BHT) against oxidative stress of Escherichia coli endotoxin (LPS) in liver. Ninety Wistar albino rats were assigned in three groups. Rats received one of the following pre-treatment previous to 5mg/kg LPS intraperitoneally: saline, L-arg (NO donor, 100mg/kg) or BHT (250 mg/kg/day), for 3 days. At second, fourth and sixth hours, plasma nitrite-plus-nitrate, circulating liver enzymes, glutathione levels, superoxide dismutase, glutathione peroxidase activities were measured. The most remarkable liver injury was evident in BHT pre-treated animals at all time points compared to L-arg pre-treated rats. While BHT enhanced superoxide dismutase activities following LPS, glutathione decreased simultaneously compared to L-arg group. Although the risk associated with the use of BHT alone in subthreshold doses appeared to be low, higher risk of liver toxicity should be considered when over-consuming this food additive in endotoxemic settings.  相似文献   

7.
To obtain insight into the protection mechanism of butylated hydroxyanisole (BHA), a widely used food preservative with anticarcinogenic properties, we investigated the effects of dietary BHA on rat hepatic and intestinal glutathione S-transferase (GST) enzyme activity, and GST isozyme levels. In the proximal small intestine and liver, BHA supplementation significantly increased GST enzyme activity as compared with controls (2.3- and 1.7-fold, respectively, P less than 0.05). GST class alpha and mu contents were significantly higher only in the small intestine (1.6-2.1-fold and 1.3-1.5-fold, respectively, P less than 0.05), whereas GST class pi was significantly induced in liver (4.6-fold, P less than 0.05).  相似文献   

8.
Toxicity of butylated hydroxytoluene in mouse following oral administration   总被引:1,自引:0,他引:1  
H Witschi  S Lock 《Toxicology》1978,9(1-2):137-146
Male Swiss--Webster mice were given 400 mg/kg of butylated hydroxytoluene ([methyl-14C]toluene) by stomach tube. Radioactivity was measured in plasma, lung, liver and kidney from 0.5 h to 10 days later. Radioactivity associated with butylated hydroxytoluene (BHT) or its metabolites was highest in plasma and all tissues examined between 1 and 12 h after administration. After 24 h, less than 1% of the administered dose remained in the lung, kidney or liver. One day after BHT, DNA synthesis in lung increased and, on days 3, 4 and 5, was 6--8 times as high as in controls. DNA content of the lungs almost doubled. Synthesis and net increase of pulmonary DNA were dose-dependent. If BHT was given orally following injection of one single dose of urethane, adenoma formation in lung was enhanced. It is concluded that BHT, given by stomach tube and in doses higher than 100 mg/kg, produces extensive cell proliferation in mouse lung and acts as a promoting agent in adenoma development.  相似文献   

9.
Although butylated hydroxytoluene (BHT) is non-mutagenic, at high doses it has recently been associated with an increased incidence of liver tumours in laboratory rodents. To establish whether chronic liver cell injury may be involved in the genesis of these tumours, BHT was administered to rats by orogastric gavage at doses of 0, 25, 250 or 500 mg/kg/day for up to 28 days and also at daily doses of 1000 and 1250 mg BHT/kg for up to 4 days (sublethal doses). The sublethal doses induced centrilobular necrosis within 48 hr, whereas administration of BHT for 7 or 28 days caused dose-related hepatomegaly and at the highest dose level induced progressive periportal hepatocyte necrosis. The periportal lesions were associated with proliferation of bile ducts, persistent fibrous and inflammatory cell reactions, hepatocyte hyperplasia and hepatocellular and nuclear hypertrophy. Biochemical changes consisted of dose-related induction of epoxide hydrolase, dose-related changes in the ratio of cytochrome P-450 isoenzymes and depression of glucose-6-phosphatase. Measurement of BHT demonstrated a dose-related accumulation in fat but not in the liver. Changes in hepatic activating and detoxifying enzyme profiles are implicated both in the mechanism of periportal hepatocyte damage and in the change of site of damage according to the dose and duration of the treatment. The persistent and active nature of the lesions in rats dosed with 500 mg BHT/kg for 28 days, combined with evidence of cell damage at doses equivalent to those associated with hepatic tumours (250 mg BHT/kg), suggests that chronic liver cell damage may be involved in their aetiology. In this and several other studies, there was no evidence that BHT causes liver damage at a dose level of 25 mg/kg/day. As this is several hundred times higher than the normal human intake, it is considered unlikely that BHT poses a threat to human health.  相似文献   

10.
Male Sprague-Dawley rats were injected intraperitoneally (i.p.) with butylated hydroxyanisole (BHA) at doses of 0, 1, 4, 16, 64, 256, 384, 576, 864, 1296 and 1944 mg/kg/day for 7 days. Deaths occurred in a dose- and time-dependent manner when BHA was given in amounts greater than 576 mg/kg. The LD50 was 881 (484-1440) mg/kg. Intracranial hemorrhage was found in the dead rats, and lung hemorrhage was observed in the survivors given BHA at doses greater than 384 mg/kg/day. Histopathologically, intra-alveolar hemorrhages, thickening of alveoli and deposition of lipids in the lungs were observed. The prothrombin index was decreased only in rats given BHA at a level of 384 mg/kg/day. These observations suggest that BHA and/or its metabolite cause pulmonary hemorrhagic damage in rats. The mechanism of hemorrhage may be different from that of bleeding induced by butylated hydroxytoluene.  相似文献   

11.
Toxic doses of butylated hydroxytoluene (BHT), a phenolic antioxidant commonly used as a food additive, are known to produce lung damage. In this study, 3 days after a single ip injection of 62.5, 215, or 500 mg/kg BHT in mice there was a dose-dependent increase in lung weight. This concentration dependence with injected BHT was accompanied by increases in lung DNA and nonprotein sulfhydryl levels and in whole lung tissue enzyme activities of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and superoxide dismutase. The increased enzyme activities are considered to correspond to inflammatory and proliferative pulmonary changes resulting from acute lung cell injury and necrosis, which have been described previously, and cannot be construed as evidence for a primary oxidant-induced pulmonary lesion. The mechanism of BHT-induced lung changes may not be related to the antioxidant property of BHT, since vitamin E, n-propyl gallate, ethoxyquin, N,N'-p-phenylenediamine, and the structurally similar compound, butylated hydroxyanisole did not appear to produce the gross anatomical or biochemical lung changes observed with BHT.  相似文献   

12.
Butylated hydroxyanisole (BHA) enhanced both the in vitro peroxidase-catalysed covalent binding of butylated hydroxytoluene (BHT) to microsomal protein and the formation of BHT-quinone methide. Eugenol, methylparaben, vanillin, guaiacol, ferulic acid and several other phenolic compounds commonly used in food and cosmetic products also enhanced the metabolic activation of BHT. BHA was the most effective compound tested. Microsomes from lung, bladder, kidney medulla and small intestine of various animal species, including man, were also able to support this interaction of BHA and BHT using either hydrogen peroxide or arachidonic acid as the substrate. These in vitro observations were extended to an in vivo mouse lung model. Subcutaneous injections of BHA significantly enhanced the lung/body weight ratio of mice given intraperitoneal injections of subthreshold doses of BHT. The toxicological implications of the interactions of BHT with other antioxidants and phenolic chemicals and their potential relevance to human risk are discussed.  相似文献   

13.
The food additive butylated hydroxytoluene (BHT) is capable of damaging centrilobular or periportal cells in the liver according to the dose and duration of treatment. The effect of two hepatotoxicity potentiating agents on the site specificity of acute cell damage was investigated in Sprague-Dawley rats. A 500 mg/kg oral dose of BHT did not cause overt hepatic necrosis or alter the cytochrome P450 concentration, but increased ethoxycoumarin-O-deethylation, implying an alteration in the ratio of P450 isoenzymes. Pretreatment with either phenobarbitone (3 X 80 mg/kg, ip) or the glutathione depleting agent buthionine sulfoximine (900 mg/kg, ip) produced liver necrosis in approximately 50% of animals: mainly in centrilobular areas, but with some necrosis in midzonal or periportal areas. Phenobarbitone and BHT did not significantly change the cytochrome P450 concentration, but did alter the ratio of P450 isoenzymes. In phenobarbitone-pretreated rats centrilobular hepatocyte damage was clearly localized in cells with high immunocytochemical staining for the cytochrome P450IIB subfamily. Buthionine sulfoximine and BHT reduced the cytochrome P450 concentration without reducing ethoxycoumarin-O-deethylase activity, implying a different alteration in the ratio of P450 isoenzymes. These results indicate that phenobarbitone-inducible enzymes are capable of activating high doses of BHT to reactive oxidizing intermediates, which in the absence of adequate glutathione can cause cell death. Enzymes of the P450IIB subfamily are implicated in this mechanism.  相似文献   

14.
Pretreatment with buthionine sulfoximine (BSO; 900 mg/kg) induced the elevation of serum GOT and GPT activities in a non-toxic dose of butylated hydroxytoluene (BHT; 250-500 mg/kg) in rats. The elevation of serum enzyme activities was accompanied by a remarked depletion of the hepatic glutathione (GSH) concentration. In contrast, pretreatment with cysteine (100-200 mg/kg) inhibited the elevation of serum enzyme activities at a toxic dose of BHT (1000 mg/kg). The effects of BSO and cysteine on BHT-induced hepatotoxicity in rats are discussed.  相似文献   

15.
When rats were fed a diet containing 0.4% (w/w) butylated hydroxytoluene (BHT), a three-fold increase in total glutathione (GSH) S-transferase activity towards 1-chloro-2,4-dinitrobenzene (CDNB) was observed in liver but not in lung or kidney. Hepatic GSH S-transferase activities towards styrene oxide (SO) and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were also increased, but to a lesser extent. Isoelectric focusing studies indicated that the activities of most of the rat liver GSH S-transferase isoenzymes were induced. Immunoprecipitation studies of the native and induced enzymes suggested that de novo synthesis of these proteins caused the increase in GSH S-transferase activity in liver. A two-fold increase in glutathione reductase activity in liver upon dietary administration of BHT was observed. Kinetic and physical properties of the native and induced enzymes were similar which may indicate that the induction is due to the synthesis of this enzyme. A significant increase in reduced glutathione (GSH) content in liver and lung was also seen in rats treated with BHT.  相似文献   

16.
H.P. Witschi 《Toxicology》1981,21(2):95-104
Male A/J mice were injected i.p. with a single dose of urethan and fed 0.75% butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) or ethoxyquin in the diet. All animals were killed 4 months after urethan and the number of lung tumors counted. Exposure to BHT, but not to BHA or ethoxyquin significantly enhanced formation of lung tumors if animals were given the BHT-containing diet once a week for 8 consecutive weeks or were kept on it continuously for 8 weeks. Prefeeding mice with BHT had no effect on tumor formation but prefeeding BHA reduced the number of tumors formed by urethan. It is concluded from this and previous work that in mouse lung BHT enhances tumor formation regardless of route of administration and over a 100-fold dose range.  相似文献   

17.
Pathology of BHA- and BHT-induced lesions   总被引:2,自引:0,他引:2  
The pathology lesions from three studies, two with butylated hydroxyanisole (BHA) and one with butylated hydroxytoluene (BHT), are reviewed. When BHA was fed at 0.5 and 2.0% of the diet to F344 rats for two years, there was an increase in epithelial hyperplasia of the forestomach at both treatment levels. Papilloma and squamous-cell carcinoma of the forestomach were increased at the 2.0% level. When BHA was fed to beagle dogs at 1.0 and 1.3% of the diet for 180 days, no lesions/tumours of the distal oesophagus or stomach could be identified either at gross necropsy or by light or electron microscopy. The BHT was fed to Wistar rats at 0, 25, 100 and 250 mg/kg body weight. At the highest dose there was an increase in the number of rats with hepatocellular adenoma and with hepatocellular carcinoma.  相似文献   

18.
The distribution of radio-labeled N-Acetyl-L-Cysteine (NAC) and its impact on glutathione (GSH) metabolism was studied in Sprague-Dawley rats following single and multiple dosing with NAC by oral gavage. Radioactivity associated with administration of (14)C-NAC distributed to most tissues examined within 1 hour of administration with peak radioactivity levels occurring within 1 hour to 4 hours and for a majority of the tissues examined, radioactivity remained elevated for up to 12 hours or more. Administration of a second dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following 1 dose. Administration of a third dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the second dose did not significantly increase tissue radioactivity further except in the skin. GSH concentrations were increased 20% in the skin and 50% in the liver after one dose of 1,200 mg/kg NAC whereas lung and kidney GSH were unaffected. Administration of a second and third dose of 1,200 mg/kg NAC at 4 hours and 8 hours after the first did not increase tissue GSH concentrations above background with the exception that skin GSH levels were elevated to levels similar to those obtained after a single dose of NAC. Glutathione-S-transferase (GST) activity was increased 150% in the kidney and 10% in the liver, decreased 60% in the skin, and had no effect on lung GST activity following a single dose of 1,200 mg/kg NAC. Administration of a second dose of 1,200 mg/kg NAC 4 hours after the first decreased skin GST activity a further 20% whereas kidney GST activity remained elevated at levels similar to those obtained after 1 dose of NAC. Administration of a third dose of NAC 4 hours after the second dose increased liver GST activity significantly as compared to background but did not affect skin, kidney, or lung GST activity. Transient decreases in glutathione reductase (GR) activity were measured in the skin and kidney in association with repeat administration of 1,200 mg/kg NAC. Glutathione peroxidase (GxP) activity was increased in the skin, kidney, and liver suggesting that oxidative stress was occurring in these tissues in response to repeat dosing with NAC. Overall, the results of this study present the possibility that NAC could provide some benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) in some tissues by increasing tissue NAC and/or cysteine levels, GSH concentrations, and GST activity. However, follow-on studies in animals are needed to confirm that oral administration of single and multiple doses of NAC can significantly reduce skin, eye, and lung toxicity associated with sulfur mustard exposure. The finding that GxP activity is elevated, albeit transiently, following repeat administration of NAC suggests that repeat administration of NAC may induce oxidative stress in some tissues and further studies are needed to confirm this finding.  相似文献   

19.
Pneumotoxicity of butylated hydroxytoluene applied dermally to CD-1 mice   总被引:1,自引:0,他引:1  
Pneumotoxicity of butylated hydroxytoluene (BHT) applied to the skin of CD-1 mice was investigated and compared with that of butylated hydroxyanisole (BHA). To 6 groups of 10 male mice and 10 female mice 0.1 ml of dimethylsulfoxide (DMSO) solutions containing 0, 5, 10, 20, or 30 mg of BHT or 30 mg of BHA were topically applied 3 times weekly for 4 weeks. Between the 4th and 8th day BHT-treated mice exhibited respiratory distress with subsequent dose-dependent mortality. At autopsy dead animals were found to have congestion and enlargement of the lung with oozing of froth from the trachea. Histologically, collapse of the alveoli and dilatation of the alveolar ducts associated with degeneration or necrosis of type I alveolar epithelial cells were evident. The lethal effect of BHT was more manifest in female than in male mice. In contrast, none of the BHA-treated or control mice showed lung abnormalities. In another series of experiments to study the species difference of BHT pneumotoxicity, F-344 rats of both sexes and male Syrian golden hamsters were exposed to BHT by dermal application 3 times weekly for 4 weeks at a dose of 240 mg in rats or 480 mg in hamsters. However, no pulmonary alterations were observed in either species.  相似文献   

20.
The effect of 1-cyano-3,4-epithiobutane (CEB) on glutathione (GSH) metabolism was investigated in rat liver, kidney and pancreas. Male Fischer 344 rats were gavaged with a single dose (125 mg/kg body weight or 50 mg/kg body weight) of CEB. Tissue samples were taken for histological examination, determination of GSH and oxidized glutathione (GSSG) concentrations and gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase (GST) activities. Urine samples were analysed for non-protein thiol (NP-RSH) content. The high dose of CEB induced hepatic GSH depletion followed by increased GSH. The low dose of CEB induced elevated hepatic GSH by 12 hr without depletion. Renal GSH was increased with both doses without an observed depletion phase. Renal tubule epithelial cell death was observed only with the high dose of CEB, but both doses caused renal proximal tubule karyomegaly. Pancreatic GSH content was unaffected. No alterations of GSSG were observed. GST activity was unaffected in any tissue. Renal GGT activity was decreased at 12 hr with both doses and at 24 and 48 hr with the high dose. Urinary NP-RSH excretion was increased with both doses. Depletion of hepatic GSH concurrent with increased urinary NP-RSH excretion suggests that conjugation with GSH is a significant pathway in CEB metabolism.  相似文献   

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