摘要:

AbstractThe induction of phosphatidylcholine (PC) biosynthesis via the CDPcholine pathway in lung and liver of rats has been shown following the intratracheal administration of 1,1,1‐trichloro‐2m2‐bis(p‐chlorophenyl) ethane (DDT) (5 mg/100 g body weight) and endosulfan (1 mg/100 g body weight) for 3 days. Controls received only the vehicle solution (groundnut oil, 0.1 ml/100 g body weight). The treatment of DDT and endosulfan significantly increased the PC contents and the incorporation of radioactive [methyl‐3H]choline into PC of lung and liver microsomes. The incorporation of radioactive [methyl‐14C]methionine into microsomal PC of lung and liver was not affected significantly by treatment with either of the insecticides. 1,4,5,6,7‐hexachloro‐5‐norbornene‐2,3‐dimethano cyclic sulfite (endosulfan) administration significantly increased the activity of choline kinase and phosphocholine cytidylyl‐transferase (both cytosolic and microsomal) of lung, whereas DDT increased the activity of only the latter. In liver, both DDT and endosulfan administration significantly increased the activity of choline kinase and phosphocholine cytidylyltransferase (both cytosolic and microsomal). However, the activity of phosphocholinetransferase was not affected in both lung and liver microsomes of rats treated with these insecticides. The PC precursor pool sizes, choline and phosphorylcholine, of lung and liver tissues were not altered by DDT and endosulfan treatments. The present results suggest that the increased level of PC and incorporation of radioactive [methyl‐3H]choline into microsomal PC could be the result of increased activity of choline kinase and phosphocholine cytidylyltransferase of lung and liver of rats following intratracheal administrat

ISSN:0887-2082    

DOI:10.1002/jbt.2570040402

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe potentiation of CCl4toxicity by pre‐exposure to chlordecone (CD) is well established. Chlordecone‐induced metabolism of CCl4and suppressed hepatocellular repair have been offered as possible mechanisms for this potentiation. Recent work using the partially hepatectomized (PH) rat as a model for an actively regenerating liver has provided supportive evidence for the latter hypothesis. The present study was initiated to determine if metabolism and disposition of14CCl4is altered in the PH rat, and if this is a contributing factor to the reported protective effect afforded by the PH procedure. Male Sprague‐Dawley rats (150–175 g) maintained on dietary CD (10 ppm) for 15 days were partially hepatectomized or sham‐operated (SH) on day 15. Another group of CD‐pretreated rats received 0.9% CoCl2(60 mg/kg, sc, qd for 2 days) in lieu of the surgical procedure. On day 16 the rats were challenged with a single dose of CCl4(100 μL/kg, ip) containing 20 μCi14CCl4. A radiolabel inventory consisting of exhaled14CCl4,14CO2production, total hepatic14C, free14CCl4and covalently bound14C was taken over a 6‐hr time period. Lipid peroxidation and serum enzyme activities [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured as indices of toxicity. Neither CD pretreatment alone nor CoCl2treatment alone produced significant alterations in metabolism of low dose (100 μl/kg) CCl4. No significant difference in14CCl4recovery or14CO2production was detected for PH versus SH rats. Hepatic14CCl4‐derived14C (per gram tissue) was greater in PH rats. Values for free14CCl4, covalently bound14C, and lipid peroxidation were similar for SH and PH rats. The data suggest that metabolism and disposition of CCl4are not altered by PH. Thus the PH rat is a valid model for studying the CD + CCl4interaction in an actively regenerating liver, and the protection afforded by partial hepatectomy is not due to a reduction in hepatic uptake or bio

ISSN:0887-2082    

DOI:10.1002/jbt.2570040403

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe purpose of this study was to determine the relative roles of viral‐induced interferon (IFN) and viral infection of the liver in mouse cytomegalovirus (MCMV)‐induced depression of cytochrome P‐450 (cyt P‐450) levels and enhancement of pentobarbital‐induced sleeping time (PEN‐ST). This was done by establishing the temporal relationship among the IFN response, viral infection of the liver, suppression of cyt P‐450 levels, and enhancement of PEN‐ST, by determining the effect of anti‐IFN antibody treatment on all of these responses, and by manipulating factors known to influence viral pathogenesis and host response to virus such as animal age, virulence of the virus, and dose of virus. In general, manipulation of these factors toward increased stimulation of host immune responses resulted in greater depression of cyt P‐450. The data are consistent with the hypothesis that some IFN‐dependent mechanism may have contributed to the effects of MCMV infection on both cyt P‐450 levels and PEN‐ST; however, the temporal relationship among the various responses measured following viral infection suggested that the effect of the IFN response may be indirect and due to modulation of other host defense mechanisms. Use of anti‐IFN antisera to definitively establish a role for IFN in the effects observed here proved unsuccessful. Effects on PEN‐ST and cyt P‐450 levels did not appear to be related to the magnitude of infection in the liver. Because suppression of cyt P‐450 levels and enhancement of PEN‐ST were not always parallel, it is possible that the enhanced sensitivity to pentobarbital observed in infected mice was the cumulative result of effects on cyt P‐450 as well as other components involved in the di

ISSN:0887-2082    

DOI:10.1002/jbt.2570040404

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe imidazole antifungal agents give rise to adverse reactions and clinically relevant drug interactions. This is due to lack of specificity of the antifungal agents that interact avidly not only with the fungal but also with mammalian cytochrome P‐450 proteins. A computer graphic technique capable of predicting the interaction of these structurally‐related imidazoles with fungal and mammalian cytochrome P‐450 proteins is described. This prediction is achieved by comparing the molecular conformation of these drugs with lanosterol, the substrate of the fungal cytochrome P‐450, and with phenobarbitone, an inducing agent of a family of mammalian cytochrome P‐450, toward which the antifungal agents show highest inhibitory

ISSN:0887-2082    

DOI:10.1002/jbt.2570040405

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

年代:1989

数据来源: WILEY

摘要:

AbstractAcetaminophen (50 mg/kg body weight) was administered by iv injection to pregnant guinea pigs (60–65 days of gestation) and by ip injection to cesarian‐derived term (67 days of gestation) pups. At suitable time intervals after treatment, the concentrations of drug, glucuronide (GLU), and sulfate (SO4) in blood plasma, urine, and bile were measured by high‐performance liquid chromatography (HPLC). At 60–65 days of gestation, guinea pig fetuses formed both GLU and SO4, an approximate ratio of 2:1 being observed with mean concentrations of the order of 43 and 27 μg/mL being measured for GLU and SO4, respectively at 180 min post‐treatment. At the same time interval, the major detoxification product found in the blood plasma of the pregnant dams was GLU (104 μg/mL) with only minute amounts (4.2 μg/mL) of SO4being detected. In cesarian‐derived and acetaminophen‐treated pups, euthanized at 2 or 4 hr post‐treatment, plasma levels of GLU were approximately twofold higher relative to the concentration of SO4at both time intervals. Significant differences were not observed in either bile or urine at 2 hr post‐treatment but by 4 hr after treatment the levels of GLU found in the bile and urine were two‐ or threefold higher than those of SO4. In contrast to the adult guinea pig where GLU forms some 90% of the urinary excretory product and SO4accounts for only 7%, the SO4pathway of detoxification appears to be of significant importance to the fet

ISSN:0887-2082    

DOI:10.1002/jbt.2570040406

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe ability of a number of known inhibitors of catalase activity to affect cytosolic and microsomal epoxide hydrolase activitiesin vitro, measured as enzymatictrans‐stilbene oxide hydrolysis and styrene oxide hydrolysis, respectively, was investigated. Catalase and cytosolic epoxide hydrolase activities are inhibited by hydroxylated metabolites of 2‐amino‐4,5‐diphenylthiazole (DPT). The metabolite hydroxylated on the 4‐phenyl ring (4OH‐DPT) and the metabolite hydroxylated on both phenyl rings (4,5‐DIOH‐DPT) are potent inhibitors of both enzymes; the metabolite hydroxylated on the 5‐phenyl ring (5OH‐DPT) is less potent. Unmetabolized DPT has no effect on either enzyme. 4OH‐DPT inhibits, but 5OH‐DPT enhances, microsomal epoxide hydrolase activity. 4,5‐DIOH‐DPT and DPT have no effect on this enzyme. Other compounds that inhibit both catalase and cytosolic epoxide hydrolase activities, but do not inhibit microsomal epoxide hydrolase activity, are nordihydroguaiaretic acid and 2‐aminothiazole. Microsomal epoxide hydrolase activity is enhanced by 2‐aminothiazole and levamisolein vitro. Thus these inhibitors of catalase are selective epoxide hydrolase inhibitors in that they inhibit cytosolic epoxide hydrolase activity invitro, but have either no effect on, or increase the activity of, microsomal epoxide hydrolasein vitro. Conversely, the selective cytosolic epoxide hydrolase inhibitors 4‐phenylchalcone oxide and 4′‐phenylchalcone oxide do not inhibit catalase activity, nor does trichloropropene oxide, a selective m

ISSN:0887-2082    

DOI:10.1002/jbt.2570040407

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

年代:1989

数据来源: WILEY

摘要:

AbstractBioenergetics of isolated lung and heart mitochondria from adult and aged rats were examined in the presence of glutamate (NAD‐linked substrate) or succinate + rotenone (FAD‐linked substrate) following ozone exposure (3.0 ppm, 8 hr). In controls, several differences were observed between adults and aged in both organ preparations. Following exposure, all bioenergetic parameters were decreased significantly in lung preparations from both adult and aged rats. In heart mitochondria, the respiration rates in state 3 and in uncoupled state, and the ADP/O ratio were decreased significantly in both exposed age groups. The respiratory control ratio (RCR) was decreased significantly only in the aged exposed rats. These results suggest that acute exposure to high levels of ozone alters energy production in both lung and heart mitochondria of adult and aged r

ISSN:0887-2082    

DOI:10.1002/jbt.2570040408

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

年代:1989

数据来源: WILEY

摘要:

AbstractIn the presence of a source of sulfane sulfur, a cyanolysis reaction catalyzed by serum albumin may contribute to cyanide detoxication. The active site for this catalysis by serum albumin has been investigated in competition studies with ligands that have known albumin binding sites. Despite complications caused by the occurrence of multiple primary and secondary sites for many ligands, the results show that the primary sites for bilirubin, steroids, indoles, aspirin, and palmitate are distinct from that for sulfur. Laurate is a tight‐binding partial inhibitor of the cyanolysis reaction, competitive with cyanide rather than with sulfur. In view of the formal mechanism previously established for the catalyzed reaction, this result indicates that the sulfur‐cyanolysis site is probably near the site occupied by laur

ISSN:0887-2082    

DOI:10.1002/jbt.2570040409

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

年代:1989

数据来源: WILEY

摘要:

AbstractOrdinary tight‐binding inhibition in steady‐state enzyme systems is conveniently evaluated by means of the Henderson plot. This is a linear plotting form that has an ordinate intercept equal to the total enzyme concentration. However, there are two experimental situations that yield deviations from the common Henderson plot form. These are inhibitor binding in a separate, noninhibitory mode that depletes the concentration of free inhibitor, and partial inhibition, i.e., the retention of partial activity by the enzyme‐inhibitor complex. Noninhibitory depletion results in Henderson plots with elevated ordinate intercepts. Competitive partial inhibition yields a characteristic pattern of parabolic Henderson

ISSN:0887-2082    

DOI:10.1002/jbt.2570040410

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

年代:1989

数据来源: WILEY

摘要:

AbstractThe primary (and inactive) enteric metabolite of 5‐aminosalicylate is N‐acetyl‐5‐amino‐salicylate. Previous studies have demonstrated acetylation of this anti‐inflammatory agent by intestinal and bacterial homogenates. To assess the contribution of anerobic bacteria to theN‐acetylationin vivo, we have measured the production of N‐acetyl‐5‐aminosalicylate in anerobic microculture. Our results indicate that enteric bacteria play a minor role in N‐acetylation, but may contribute to the production of other metabolites of pharmacologic and t

ISSN:0887-2082    

DOI:10.1002/jbt.2570040411

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

年代:1989

数据来源: WILEY