摘要:

AbstractEvidence based on thermal lability and enzyme inhibition data suggests that the sulfoxidation of methiocarb (anN‐methylcarbamate insecticide) by rat liver microsomes is catalyzed by flavin‐containing monooxygenase(s) (FMO) and by cytochrome(s) P450 (P450). In control rats, the relative proportion is ca. 50% P450:50% FMO. Stereoselective formation of methiocarb sulfoxide from the corresponding sulfide has also been examined to compare the enantioselectivity of the two different enzyme systems. Only the FMO‐dependent sulfoxidation presents a high stereoselectivity with an enantiomeric excess of 88% in favor of the (A)‐enantiomer. Pretreatment of rats with different P450 inducers such as phenobarbital, 3‐methylcholanthrene, dexamethasone, and pyrazole did not affect, or decreased, the rate of methiocarb sulfoxidation. Stereoselectivity of the reaction was modified, mainly because of changes in the relative involvement of FMO and P450 in sulfoxidase activity in pretreated animals. The acetylcholinesterase inhibition properties of methiocarb and its main metabolites were also investigated. Racemic methiocarb sulfoxide was slightly less inhibitory (Ki = 0.216 μM−1· min−1) than methiocarb, but a 10‐fold difference was observed between the bimolecular rate constants found for the two sulfoxides produced (0.054 and 0.502 μM−1·min−1for the (A) and (B) enantiomers, respectively). © 1

ISSN:0887-2082    

DOI:10.1002/jbt.2570100402

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

年代:1995

数据来源: WILEY

摘要:

AbstractDietary indole‐3‐carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3′‐diindolylmethane, an in vivo derivative of indole‐3‐carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A‐dependent ethoxyresorufinO‐deethylase withKivalues in the low micromolar range. We now report a similar potent inhibition by 3,3′‐diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP‐specific or preferential activity assays. 3,3′‐Diindolylmethane also inhibited in vitro CYP‐mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochromecreductase. In addition, we found 3,3′‐diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3′‐diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP‐mediated activation of procarcinogens may be an indole‐3‐carbinol anticarcinogenic mechanism applicable to all species, incl

ISSN:0887-2082    

DOI:10.1002/jbt.2570100403

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

年代:1995

数据来源: WILEY

摘要:

AbstractIn the multiple‐dose bleomycin‐hamster model of pulmonary fibrosis, combined treatment with taurine and niacin blocks the increase in lung collagen deposition. We investigated the effects of taurine and niacin on lung lysyl oxidase and type I collagenase activities in this model. Hamsters were intratracheally instilled with three weekly doses of saline or bleomycin sulfate. Animals were fed either a diet containing 2.5% niacin and 2.5% taurine, or a control diet throughout the experiment. The four groups were saline‐instilled with the control diet (SCD), bleomycin‐instilled with control diet (BCD), bleomycin‐instilled with the diet containing taurine and niacin (BTN), and saline‐instilled with the diet containing taurine and niacin (STN). Animals were sacrificed at 1, 4, and 8 weeks after the last bleomycin instillation. Hydroxyproline per lung in the BCD group was significantly elevated by 38, 56, and 60% over the SCD group at 1, 4, and 8 weeks, respectively. Lysyl oxidase activity per lung in the BCD group was significantly elevated by 57.5 and 91.4% over the SCD controls at 1 and 4 week time periods, respectively. Type I collagenase activity per lung in the BCD group was significantly elevated by 65 and 80% over the SCD controls at 1 and 4 weeks, respectively. The combined treatment with taurine and niacin abolished the bleomycin‐induced increases in the lung hydroxyproline content and lysyl oxidase and collagenase activities. It was postulated that one of the mechanisms for the antifibrotic effect of taurine and niacin may be the blockage of bleomycin‐induced increases in the lung lysyl oxidase and collagenase activities. © 1995 John

ISSN:0887-2082    

DOI:10.1002/jbt.2570100404

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

年代:1995

数据来源: WILEY

摘要:

AbstractNeuropathy target esterase (NTE) is the proposed target site for the mechanism of initiation of the so‐called organophosphorus‐induced delayed polyneuropathy (OPIDP). NTE is operationally defined in this article as the phenylvalerate esterase activity which is resistant to inhibition by 40 μM paraoxon and sensitive to 250 μM mipafox. Soluble (S‐NTE) and particulate (P‐NTE) forms of NTE had first been identified in hen sciatic nerve [E. Vilanova, J. Barril, V. Carrera, and M. C. Pellín (1990).J. Neurochem., 55, 1258–1265]. P‐NTE and S‐NTE showed different sensitivities to the inhibition by several organophosphorus compounds over a range of inhibitor concentrations for a 30 or 120 minute fixed inhibition time at 37°C. S‐NTE was less sensitive to the inhibition by O,O′‐diisopropyl phosphorofluoridate (DFP), hexyl 2,5‐dichlorophenyl phosphoramidate (H‐DCP), and mipafox than P‐NTE and brain NTE, while the opposite was true for O,S‐dimethyl phosphoroamidothioate (methamidophos). For each of the four inhibitors assayed, S‐NTE showed two components of different sensitivity according to the inhibition curves fitted with exponential models. However, the inhibition of P‐NTE by mipafox, DFP, and HDCP did not show the presence of a considerable proportion of a second component. The kinetics of heat inactivation showed that P‐NTE inactivated faster and to a greater extent than S‐NTE. It is concluded that (1) sciatic nerve S‐NTE is more different from brain NTE than P‐NTE; (2) P‐NTE and S‐NTE have different sensitivities to the inhibition by the studied organophosphorous compounds; (3) the inhibition curves suggest that S‐NTE has two different enzymatic components while these are not

ISSN:0887-2082    

DOI:10.1002/jbt.2570100405

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

年代:1995

数据来源: WILEY

摘要:

AbstractEnvironmental chemicals, such as polychlorinated biphenyls (PCBs), may be atherogenic by disrupting normal functions of the vascular endothelium. To investigate this hypothesis, porcine pulmonary artery‐derived endothelial cells were exposed to 3,3′,4,4′‐tetrachlorobiphenyl (PCB 77), 2,3,4,4′,5‐pentachlorobiphenyl (PCB 114), or 2,2′,4,4′,5,5′‐hexachlorobiphenyl (PCB 153) for up to 24 hours. These PCBs were selected for their varying binding avidities with the aryl hydrocarbon (Ah) receptor and differences in their induction of cytochrome P450. PCB 77 and PCB 114 significantly disrupted, in a dose‐dependent manner, endothelial barrier function by allowing an increase in albumin transfer across endothelial monolayers. These PCBs also contributed markedly to cellular oxidative stress, as measured by 2,7‐dichlorofluorescin (DCF) fluorescence and lipid hydroperoxides, and caused a significant increase in intracellular calcium ([Ca2+]i) levels. Enhanced oxidative stress and [Ca2+]iin PCB 77‐ and PCB 114‐treated cells were accompanied by increased activity and content of cytochrome P450 1A and by a decrease in the vitamin E content in the culture medium. In contrast to the effects of PCB 77 and PCB 114, cell exposure to PCB 153 had no effect on cellular oxidation, [Ca2+]i, or endothelial barrier function. These results suggest that certain PCBs may play a role in the development of atherosclerosis by causing endothelial cell dysfunction and a decrease in the barrier function of the vascular endothelium. It is possible that interaction of PCBs with the Ah receptor and activation of the cytochrome P450 1A subfamily are involved in this pathology.

ISSN:0887-2082    

DOI:10.1002/jbt.2570100406

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

年代:1995

数据来源: WILEY

摘要:

AbstractQuinone‐induced cell death is often attributed to oxidative stress during which the formation of DNA strand breaks is thought to play an important role. In this study, extensive DNA damage was observed in human chronic myelogenous leukemic cells (K562) exposed for 15 minutes to low concentrations (15–100 μM) of the redox cycling quinones 2,3‐dimethoxy‐1,4‐naphthoquinone (2,3‐diOMe‐1,4‐NQ) and menadione. However, DNA strand breakage and cell death could not be attributed to oxidative stress as the intracellular level and redox status of the reducing equivalents NADP(H) and GSH were unaffected. The intracellular level of NAD+was found to correlate well with the extent of DNA repair (r= 0.93,P<0.02) and cell proliferation (r= 0.96,P<0.01) in cells exposed to the quinones. In contrast, a significant decrease in the level of intracellular ATP was only observed in cells exposed to menadione (50–100 μM). These results suggest that redox cycling quinones are capable of inducing DNA damage in mammalian cells by a mechanism that does not involve oxidative stress. Following DNA damage, cell death is dependent on the availability of NAD+, which may be key to the rapid repair of strand breaks. © 1995

ISSN:0887-2082    

DOI:10.1002/jbt.2570100407

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

年代:1995

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570100401

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

年代:1995

数据来源: WILEY