摘要:

AbstractThe elimination, tissue distribution, and metabolism of [1‐14C]perfluorooctanoic acid (PFOA) was examined in male and female rats for 28 days after a single ip dose (9.4 μmol/kg, 4 mg/kg). A sex difference in urinary elimination of PFOA‐derived14C was observed. Female rats eliminated PFOA‐derived radioactivity rapidly in the urine with 91% of the dose being excreted in the first 24 hr. In the same period, male rats eliminated only 6% of the administered14C in the urine. The sex‐related difference in urinary elimination resulted in the observed difference in the whole‐body elimination half‐life (t1/2) of PFOA in males (t1/2= 15 days) and females (t1/2<1 day). Analysis of PFOA‐derived14C in tissues showed that the liver and plasma of male rats and the liver, plasma, and kidney of female rats were the primary tissues of distribution. The relatively high concentration of PFOA in the male liver was further examined using an in situ nonrecirculating liver perfusion technique. It was shown that 11% of the PFOA infused was extracted by the liver in a single pass. The ability of the liver to eliminate PFOA into bile was examined in rats whose renal pedicles were ligated to alleviate sex differences in the urinary excretion of PFOA. In a 6‐hr period following IP administration of PFOA, there was no apparent difference in biliary excretion, where both males and females eliminated less than 1% of the PFOA dose via this route. We hypothesized that the sex difference in the persistence of PFOA was due to a more rapid formation of a PFOA‐containing lipid (i.e., a PFOA‐containing mono‐, di‐, or triacylglycerol, cholesteryl ester, methyl ester, or phospholipid) in the male rat. Also, the increased urinary elimination of PFOA in females may have been due to increased metabolism to a PFOA‐glucuronide or sulfate ester. However, no evidence that PFOA is conjugated to form a persistent hybrid lipid was obtained, nor were polar metabolites of PFOA in urine or bile detected. In addition, daily urinary excretion of fluoride in male and female rats before or after PFOA treatment were similar, suggesting that the parent compound is not defluorinated. Thus, the more rapid elimination of PFOA from female rats is not due to form

ISSN:0887-2082    

DOI:10.1002/jbt.2570060202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractAcetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss‐Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum isocitrate dehydrogenase (SICD) activities were monitored after APAP and APAP + AP or AS dosing. There were significant reductions in serum transaminase and SICD activities in the APAP‐ + ascorbate ester‐treated animals as compared to APAP‐positive controls. Oral coadministration of APAP with AP or AS did not prevent the initial hepatic GSH depletion (15 min‐4 hr postdosing). However, hepatic GSH content began to rise in the APAP + AS or AP‐treated animals at 4 hr and reached control values within 12 hr postdosing. Urinary mercapturate conjugates were also significantly higher in the APAP + AP or AS‐treated animals as compared to APAP alone when measured over a 60‐min postdosing period. Plasma sulfobromophthalein (BSP) retention was approximately eight times higher in APAP‐treated animals as compared to the APAP + ascorbate ester treatments indicating maintenance of hepatic excretory functions in presence of AP or AS. Prior depletion of hepatic GSH by diethyl maleate (DEM) did not alter hepatoprotective effects of AP or AS in the presence of APAP. Hepatic ascorbate levels also peaked at 4 hours after APAP + AP or AS treatments. The possible role of L‐ascorbic acid esters in GSH regeneration following co‐administration of a hepatotoxic dose

ISSN:0887-2082    

DOI:10.1002/jbt.2570060203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractHepatocytes isolated from phenobarbital‐pretreated and naive male Sprague‐Dawley rats were preincubated with 80 μMN, N‐bis (2‐chloroethyl)‐N‐nitrosourea and subsequently exposed to varying concentrations of menadione. We observed that the reduced glutathione levels of the hepatocytes isolated from the sodium phenobarbital(PB)‐pretreated, but not the naive rats, recovered to near‐control levels after exposure to 200 μM menadione. Since this recovery occurred in the presence ofN, N‐bis (2‐chloroethyl)‐N‐nitrosourea (an inhibitor of glutathione reductase), we hypothesized that this represented a PB‐mediated increase in de novo synthesis of glutathione. To test this hypothesis and to further assess the possible contribution of glutathione reductase in the recovery of the glutathione levels, we preincubated hepatocytes isolated from PB‐pretreated and naive rats with 2 mM buthionine sulfoximine, with or withoutN, N‐bis (2‐chloroethyl)‐N‐nitrosourea. Following exposure to menadione, samples were periodically removed for glutathione assessment. Consistent with our hypothesis, the addition of buthionine sulfoximine abrogated the ability of the PB‐pretreated hepatocytes to restore glutathione levels following a menadione challenge. Buthionine sulfoximine in combination withN, N‐bis (2‐chloroethyl)‐N‐nitrosourea completely abolished hepatocellular glutathione homeostasis for all of the concentrations of menadione employed. The findings from this investigation underscore the importance of phenobarbital‐mediated increases in glutathione synthesis, as well as the enhanced levels of glutathione reductase, in maintaining the pool of reduced glutathione and ultimately mitigating the consequences of oxidative stress. In addition, these findings suggest that PB pretreatment increases the reserve capacity of the hepatocyte for glutathione synthesis via a hitherto undescribed hormetic mechanism, a reserve expressed fully on

ISSN:0887-2082    

DOI:10.1002/jbt.2570060204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractThe haloacetonitrile, dibromoacetonitrile (DBAN), is a direct‐acting genotoxic agent that has been detected in drinking water. In a time course study, male Sprague‐Dawley rats were treated with DBAN (75 mg/kg PO), and killed at 0.5, 1, 2, and 4 hr after treatment. In a dose response study, animals were treated orally with various doses of DBAN (25, 50, 75, and 100 mg/kg) and killed at one‐half hour after treatment. Control animals received 1 ml/kg PO of the vehicle dimethyl sulfoxide (DMSO). In both experiments blood and organs were collected and stored at −80°C until the time of analysis. At 0.5 hr after treatment, a single oral dose of DBAN caused a significant decrease of glutathione (GSH) concentrations in liver (54% of control) and stomach (6% of control). Hepatic GSH depletion was maximal at 0.5 hr and rebound to the control levels by 4 hr. In contrast, gastric GSH concentrations remained low at all time points. DBAN caused an insignificant change in both kidney and blood GSH levels. DBAN significantly inhibited glutathione‐S‐transferase (GST) activity in liver and stomach. Hepatic GST inhibition was maximal (34% of control) at 2 hr and minimal (80% of control) at 4 hr. Meanwhile, in the stomach GST activity was inhibited at 1 hr (60% of control) and remained low at all times after treatment. Both GSH depletion and GST inhibition were dose‐dependent. This study indicates that GSH and GST play an important role in the metabolism and detoxification of DBAN in rats. The prolonged depletion of GSH and inhibition of GST in the gastrointestinal (GI) tissues suggest that the GI tract is a major target for

ISSN:0887-2082    

DOI:10.1002/jbt.2570060205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractThe drug‐metabolizing enzymes of olfactory and respiratory epithelium of cattle were determined. The data of nasal tissues were compared to those of bovine liver. Both oxidative and nonoxidative enzyme activities were investigated. Many compounds including testosterone were used as substrates for the P450‐dependent monooxygenase activities. The results demonstrated that the P450 content and all the activities assayed including reduced nicotinamide adenine dinucleotide phosphate (NADPH)‐cytochrome P450 reductase were much higher in the olfactory than in the respiratory mucosa and for some activities (hexamethyl‐phosphoramide and dimethylnitrosamineN‐demethylase, aniline hydroxylase, and ethoxycoumarinO‐deethylase) the values in the olfactory tissue were even markedly higher than those of liver. Also the activities of some nonoxidative enzymes such as glutathioneS‐transferase, uridine 5′‐diphosphate (UDP)‐glucuronyl‐transferase, and epoxide hydrolase were higher in the olfactory than in the respiratory mucosa but lower than in liver. The results taken together suggest that the olfactory and respiratory epithelium of cattle, which contain in addition to a wide array of nonoxidative enzymes multiple forms of P450, can be useful and easily available tissues to study the biotrans‐formatio

ISSN:0887-2082    

DOI:10.1002/jbt.2570060206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractEffects of isoflurane on the DNase I activity in an isolated enzyme preparation and in the DNase I‐globular (G) actin complex were investigated. DNase I, DNase I‐G actin complex, and G actin were exposed to various (0.2–4.0 vol%) isoflurane concentrations for 180 min. Thereafter, DNase I activity was determined. DNase I activity was inhibited in relation to time and concentration of isoflurane exposure. At concentrations ranging from 0.2 to 1.0 vol% of isoflurane inactive DNase I was activated in the DNase I‐G actin complex. The DNase I inhibitor G actin showed a reduced capability to inhibit DNase I following isoflurane exposure. Albumin can inhibit the DNase I inactivation possibly by competition in the reactions between DNase I/albumin and isoflurane. After exposure to isoflurane the absorption maximum of DNase I was identical with the absorption maximum of heat‐denaturated DNase I. The results suggest a mechanism by which isoflurane may affect DNA in an indirect way at concentrations to which the patient is exposed during clinical a

ISSN:0887-2082    

DOI:10.1002/jbt.2570060207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractIn this study, we have characterized the covalent binding of [14C]‐2‐chloro‐4‐acetotoluidide (CAT) radioactivity to microsomes of starling liver and kidney. The maximal velocity (Vmax) of covalent binding and apparent Michaelis constant (Km) for both tissues were similar. The Vmaxfor liver and kidney were 52.8 and 68.9 pmol/min/mg protein, and the apparent Kmswere 0.54 and 0.87 mM, respectively. The covalent binding of radioactivity to heat‐denatured microsomes of liver and kidney was reduced by 62% and 15%, respectively. Incubation at 0°C reduced the binding by 80% to liver and 70% to kidney microsomes. Absence of nicotinamide adenine dinucleotide phosphate (NADP) and molecular O2reduced the binding to liver microsomes by 36 and 53%, as opposed to 28% increase and 26% decrease in binding to kidney microsomes, respectively. Inducers of cytochrome P450monooxygenase (P450), phenobarbital, and 3‐methylcholanthrene (3‐MC), had opposite effects on the covalent binding of [14C]‐CAT radioactivity to hepatic and renal microsomes. Phenobarbital increased the binding to hepatic microsomes by 100% and had no effect on binding to renal microsomes. 3‐MC, on the other hand, increased the binding to kidney microsomes by threefold and had no effect on the binding to hepatic microsomes. SKF 525A, an inhibitor of P450, inhibited the binding to hepatic microsomes by 60% at 0.5 mM but failed to have any effect on binding to renal microsomes. α‐Naphthoflavone, another inhibitor of P450, had no effect on the covalent binding of [14C]‐CAT radioactivity to microsomes of either tissue. Addition of cysteine and glutathione in the incubation mixture inhibited the covalent binding of radioactivity to both liver and kidney microsomes in a concentration‐dependent manner. It was concluded that hepatic and renal microsomes of starling behave differently with respect to the effects of P450inducers and inhibitors, heat denaturation, NADPH dependence, and presence of molecular oxygen on bioactivation of [14C]‐CAT and its subsequent covalent bin

ISSN:0887-2082    

DOI:10.1002/jbt.2570060208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractThe possible role of glutathioneS‐transferases (GST) in detoxification of fatty acid epoxides generated during lipid peroxidation has been evaluated. Present studies showed that cytosolic human glutathioneS‐transferases belonging to α, H, and μ classes isolated from human liver and lung catalyzed the conjugation of glutathione and 9,10‐epoxystearic acid. The product of enzymatic reaction, i.e., conjugate of GSH and epoxystearic acid, was isolated and characterized. The Michaelis constant (Km) values of the α, μ, and π classes of GSTs for 9,10‐epoxystearic acid were found to be 0.47, 0.32 and 0.80 mM, respectively, whereas the maximal velocity (V max) values for the α, μ, and π classes of GSTs were found to be 142, 256, and 52 mol/min/mol, respectively. These results indicate that even though 9,10‐epoxystearic acid is a substrate for all the three classes of GSTs, the μ class isozymes have maximum activity toward this substrate and may preferentially metabolize fatty acid epoxides more effectively as compared to the oth

ISSN:0887-2082    

DOI:10.1002/jbt.2570060209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractContent of nonprotein sulfhydryls (NPSH) was found to be higher in rat renal cortex than in external medulla and papilla. Administration of bromoethylamine (BEA), at a dose that produces extensive papillary necrosis and minor effects in the other renal segments, induced a significant reduction in NPSH levels of renal cortex and external medulla, with no changes in the papilla. Treatment withN‐acetyl‐L‐cysteine (NAC) elicited an increase in papillary NPSH and a decrease in the cortex, with opposite changes being observed with an amino acid mixture of glutamine, glycine, and cystine (AM). Similar results were found in animals pretreated with NAC or AM prior to BEA intoxication. These pretreatments protect the cortex, external medulla, and papilla from the necrosis induced by BEA. It is suggested that protection of BEA‐induced renal necrosis by NAC or AM pretreatments might be due to different mechanisms, with NPSH playing direct or indirect roles, respe

ISSN:0887-2082    

DOI:10.1002/jbt.2570060210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570060211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY