摘要:

AbstractPeroxidatic metabolism of benzo(a) pyrene‐7,8‐dihydrodiol by calcium containing extracts of rat uteri was investigated. Covalently bound and soluble metabolites of benzo(a)pyrene‐7,8‐dihydrodiol were quantitated by radiometry and high performance liquid chromatography, respectively1Uterine extracts incubated with benzo(a)pyrene‐7,8‐dihydrodiol activated this proximate mutagen to protein binding metabolite(s).2Hydrogen peroxide increased the protein binding and yielded a substantial amount of benzo(a)pyrene‐trans‐anti‐tetrahydrotetrol, suggesting the peroxyl‐type free‐radical epoxidation process.3The results indicate that rat uterine peroxidase is able to catalyze free‐radical activation of benzo (a)pyrene‐7,8‐dihydrodiol by epoxidation to its 9,10‐dihydrodiolepoxide, a known ul

ISSN:0887-2082    

DOI:10.1002/jbt.2570050302

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

年代:1990

数据来源: WILEY

摘要:

AbstractWe have studied the activation of aflatoxin B1by hamster liver microsomes and purified hamster cytochrome P‐450 isozymes using aumumutagen test. The hamster liver microsomes or S‐9 fractions were much more active than rat liver microsomes or S‐9 fractions in the activation ofumugene expression by aflatoxin B1metabolites. 3‐Methylcholanthrene treatment increased aflatoxin B1activation by hamster liver microsomes. Two major 3‐methylcholanthrene‐inducible cytochrome P‐450 isozymes, P‐450 MC1 (IIA) and P‐450 MC4 (IA2), were purified from 3‐methylcholanthrene‐treated hamster liver microsomes, and the metabolism of aflatoxin B1by these two cytochromes was studied. In the reconstituted enzyme system, both P‐450 MC1 and P‐450 MC4 were highly active in the activation of aflatoxin B1, and antibodies against these P‐450s specifically inhibited these activities. Antibody against P‐450 MC1 inhibited the activation of aflatoxin B1by 20% in the presence of 3‐methylcholanthrene‐treated hamster liver microsomes. In contrast, antibody against P‐450 MC4 stimulated the activity by 175%. These results indicated that hamster P‐450 MC1 might convert aflatoxin B1to more toxic metabolite(s), whereas P‐450 MC4 might convert aflatoxin B1to less toxic metabolite(s), than aflatoxin B1in liver microsomes. The metabolite(s) produced by both hamster cytochrome P‐450 MC1 and

ISSN:0887-2082    

DOI:10.1002/jbt.2570050303

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

年代:1990

数据来源: WILEY

摘要:

AbstractPrevious studies have shown that rats treated with 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) show signs of toxicity that are similar to the responses of animals to a vitamin A‐deficient diet. These include hypophagia, loss of body weight, loss of hepatic vitamin A, and accumulation of renal retinoids. Male Sprague‐Dawley rats treated with 10, 30, or 100 nmol/kg of TCDD accumulated renal vitamin A, with retinyl palmitate concentrations reaching 8 times those of control animals, similar to that of male rats fed a vitamin A‐free diet for 26 days. Acyl CoA:retinol acyltransferase (ACARAT) activities in both TCDD‐treated rats and rats fed a vitamin A‐free diet for 26 days were similarly elevated, and were strongly and positively correlated with the renal retinyl palmitate concentrations. Retinol concentrations in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet were only slightly elevated when compared to control rats. We suggest that accumulation of retinyl esters in the kidneys of rats treated with TCDD or fed a vitamin A‐free diet occurs as a result of increased rates of ret

ISSN:0887-2082    

DOI:10.1002/jbt.2570050304

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

年代:1990

数据来源: WILEY

摘要:

AbstractMethylglyoxal (MG), a dietary mutagen, is present in various frequently consumed beverages and foods and in cigarette smoke. A combination of S1nuclease hydrolysis and alkaline unwinding assay was used to demonstrate the formation of single‐strand breaks and interstrand cross‐links in DNA upon treatment with MG. Calf thymus DNA, when treated with increasing concentrations of MG, showed an increasing degree of S1nuclease hydrolysis. It also showed the formation of an increasing number of strand breaks per molecule as determined by an alkaline unwinding assay. Incubation of DNA with relatively higher concentrations of methylglyoxal or prolonged treatment gave increased thermal melting temperatures and an enhanced rate of reannealing after thermal denaturation. These results indicated the formation of interstrand cross‐links. Upon treatment with MG, A‐T base pair depleted DNA showed a reduced number of single‐strand break formation. It also showed a significantly lower decrease inTmas compared with MG‐treated normal DNA. These results showed that under the conditions used, MG primarily reacts with A‐T base pairs

ISSN:0887-2082    

DOI:10.1002/jbt.2570050305

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

年代:1990

数据来源: WILEY

摘要:

AbstractThe ability of two novel antioxidants, U‐74,006F and U‐78,517G, as well as the known antioxidantN,N′‐diphenyl‐p‐phenylenediamine to inhibit lipid peroxidation induced by carbon tetrachloride (CCl4) was investigated in Aroclor 1254‐induced rat hepatic microsomes. All three compounds completely inhibited lipid peroxidation in microsomes as measured by the formation of thiobarbituric acid reactive substances (TBARS). Inhibition of lipid peroxidation was not a function of decreased bioactivation of CCl4, as the compounds did not substantially inhibit benzphetamineN‐demethylase activity or covalent binding of [14‐C]CCl4to lipid or protein. Parallel studies examined the hepatoprotective effects of the compoundsin vivo. Rats were pretreated with antioxidant or vehicle prior to administration of CCl4(300 or 600 μL/kg i.p.). Sera were collected 24 h postadministration of CCl4and analyzed for alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities and total bilirubin. Administration of CCl4produced elevations in ALT, moderate changes in bilirubin, and no change in ALP activities. Histological examination of CCl4‐treated livers revealed lipidosis and centrilobular necrosis. The antioxidants partially improved the clinical chemistry parameters, but had minimal effects on the histological lesion. In contrast to the complete inhibition of lipid peroxidation observed in thein vitrostudies, none of the antioxidants markedly protected against CCl4‐i

ISSN:0887-2082    

DOI:10.1002/jbt.2570050306

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

年代:1990

数据来源: WILEY

摘要:

AbstractA hepatic green pigment, inhibitory toward ferrochelatase, has been isolated from the liver of mice treated with griseofulvin, isogriseofulvin, or 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine and has been shown to exhibit identical chromatographic characteristics to authenticN‐methyl protoporphyrin. All four possible structural isomers have been demonstrated, and each drug produced primarily the same isomer.N‐Methyl protoporphyrin has also been found in very small amounts in the liver of untreated mice, but the isomeric composition appeared to differ from that of the drug‐inducedN‐methyl protoporphyrin.Intraperitoneal administration of 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine to female C3H / He / Ola and NIH / Ola inbred mice produced a marked dose‐related loss of hepatic ferrochelatase activity, which was identical in magnitude in the two strains. Induction of hepatic 5‐aminolevulinate synthase (ALA‐S), and accumulation of liver protoporphyrin, however, were greater in C3H / He / Ola mice. The strain difference in ALA‐S response was most marked when inhibition of ferrochelatase (the “specific” effect of the drug) was maximal, and this suggests that a genetic variation exists in the sensitivity of ALA‐S to a second drug action, the so‐called nonspecific action, which is shared by many lipid‐soluble compounds.Male mice of three strains accumulated greater amounts of hepatic protoporphyrin than females after treatment with griseofulvin, yet no significant difference was found between the two sexes in the extent of ferrochelatase inhibition. Stimulation of ALA‐S activity was slightly greater in males, but when porphyria was very marked, ALA‐S activities were significantly lower in this sex. Our results indicate a biphasic relationship between ALA‐S activity and porphyrin accumulation, with a depression of the activity of the enzyme occurring

ISSN:0887-2082    

DOI:10.1002/jbt.2570050307

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

年代:1990

数据来源: WILEY

摘要:

AbstractSoman (pinacolyl methylphosphonofluoridate) not only increases acetylcholine levels by inhibiting cholinesterases, it also alters the levels of some other neurotransmitters including norepinephrine, dopamine, and serotonin. Soman also causes an alteration in the activities of the enzymes metabolizing norepinephrine when it is administered to animals. Because these alterations may result from indirect effects on the enzymes, the effects of in vitro application of soman on catechol‐O‐methyl‐transferase (COMT) and monoamine oxidase (MAO) activities in rabbit tissues were investigated. Enzyme activities were determined in rabbit lung, liver, cerebellum, cerebrum, brain stem, mesenteric artery, pulmonary artery, renal artery, central ear artery, thoracic aorta, and diaphragm. MAO and COMT activities were not affected by soman in any tissues tested, except the lung and liver, where the activity of COMT was increased (p<0.05). Thus, reported effects of soman in vivo on norepinephrine, dopamine, or serotonin concentrations, and MAO and COMT activities do not seem to result from direct effects on the activities of these aminemetabolizing en

ISSN:0887-2082    

DOI:10.1002/jbt.2570050308

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

年代:1990

数据来源: WILEY

摘要:

AbstractDisturbances in intracellular calcium homeostasis may play a role in the injury induced by various haloalkene cysteine conjugates. The effects ofS‐(1,2,3,4,4‐pentachloro‐1,3‐butadienyl)‐L‐cysteine (PCBC),S‐(1,2‐dichlorovinyl)‐L‐cysteine (DCVC), andS‐(1,1,2,2‐tetrafluoroethyl)‐L‐cysteine (TFEC) on cytosolic free calcium levels were examined in suspensions of rat renal proximal tubules. Cytosolic free calcium levels, measured with fura 2, in control tubules, were 112 ± 3 nM and increased more than 200% within 1 minute after exposure to the calcium ionophore ionomycin (0.005 mM). PCBC (0.1 mM) increased cytosolic free calcium levels 18% after 5 minutes, while tubular oxygen consumption was unaffected. DCVC (1 mM) did not alter tubular cytosolic free calcium levels or oxygen consumption under similar conditions. TFEC (1 mM) increased cytosolic free calcium levels 36%, had no effect on basal oxygen consumption, and decreased nystatin‐stimulated oxygen consumption 30% after 5 minutes. TFEC increased cytosolic free calcium levels in tubules incubated in a nominally calcium‐free buffer but not in a calcium containing buffer in the presence of EGTA. The data suggest that the TFEC‐induced increase in cytosolic free calcium levels may result from an influx of extracellular calcium or from inhibition of calcium efflux. The increase in cytosolic free calcium levels preceded changes in basal oxygen consumption in tubules exposed to PCBC and TFEC. This study shows that an increase in cytosolic free calcium levels is an early event following P

ISSN:0887-2082    

DOI:10.1002/jbt.2570050309

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

年代:1990

数据来源: WILEY

摘要:

AbstractThe oxidation of uroporphyrinogen, an intermediate of the heme biosynthetic pathway, by methylcholanthrene‐inducible isozyme(s) of cytochrome P‐450 has been proposed to play a role in the development of chemically induced uroporphyria. Prior work from this laboratory [10] indicated that although addition of 3,4,3′,4′‐tetrachlorobiphenyl is required for uroporphyrinogen oxidation by methylcholanthrene‐induced chick embryo liver microsomes, this biphenyl is not required for the oxidation catalyzed by hepatic microsomes from methylcholan‐threne‐induced rodents. Here we investigated whether rodent microsomes catalyze uroporphyrinogen oxidation without addition of 3,4,3′,4′‐tetrachlorobiphenyl because the chemical used as an inducer remains bound to cytochrome P‐450. Hepatic microsomes containing almost no residual inducer were isolated from rats treated with a low dose of 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). These microsomes oxidized uroporphyrinogen at high rates without addition of 3,4,3′,4′‐tetrachlorobiphenyl. Inducerfree microsomal cytochrome P‐450 was also obtained by inducing cytochrome P‐450 in rats and mice with isosafrole, which was then removed from the isolated microsomes by butanol treatment. This procedure resulted in microsomes with high activity for uroporphyrinogen oxidation. Furthermore, addition of chlorobiphenyl to these inducer‐free microsomes was inhibitory. Hepatic microsomes from isosafroleinduced C57BL / 6 and DBA mice, rendered inducerfree by butanol treatment, oxidized uroporphyrinogen at the same rate even though these two strains differ markedly in their susceptibility to chemically induced uroporphyria. We conclude that uroporphyrinogen oxidation is catalyzed by

ISSN:0887-2082    

DOI:10.1002/jbt.2570050310

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

年代:1990

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570050311

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

年代:1990

数据来源: WILEY