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1.
Panoutsopoulos GI 《In vivo (Athens, Greece)》2004,18(6):779-786
BACKGROUND: 2-Phenylethylamine is an endogenous amine, which acts as a neuromodulator of dopaminergic responses. Exogenous 2-phenylethylamine is found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. MATERIALS AND METHODS: The present investigation examined the metabolism of 2-phenylethylamine to phenylacetic acid, via phenylacetaldehyde, in freshly prepared and cryopreserved liver slices. Additionally, it compared the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase by using specific inhibitors for each oxidizing enzyme. RESULTS: In freshly prepared and cryopreserved liver slices, phenylacetic acid was the main metabolite of 2-phenylethalamine. In freshly prepared liver slices, phenylacetic acid was completely inhibited by disulfiram (inhibitor of aldehyde dehydrogenase), whereas isovanillin (inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (inhibitor of xanthine oxidase) had no effect. In cryopreserved liver slices, isovanillin inhibited phenylacetic acid by 85%, whereas disulfiram inhibited acid formation to a lesser extent and allopurinol had no effect. CONCLUSION: In liver slices, 2-phenylethylamine is rapidly oxidized to phenylacetic acid, via phenylacetaldehyde, by aldehyde dehydrogenase and aldehyde oxidase with no contribution from xanthine oxidase. 相似文献
2.
Aromatic aldehydes are good substrates of aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. However, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase activities in the oxidation of isovanillin in separate preparations and also in freshly prepared and cryopreserved liver slices. The oxidation of isovanillin was also examined in the presence of specific inhibitors of each oxidizing enzyme. Minimal transformation of isovanillin to isovanillic acid was observed in partially purified aldehyde oxidase, which is thought to be due to residual xanthine oxidase activity. Isovanillin was rapidly metabolized to isovanillic acid by high amounts of purified xanthine oxidase, but only low amounts are present in guinea pig liver fraction. Thus the contribution of xanthine oxidase to isovanillin oxidation in guinea pig is very low. In contrast, isovanillin was rapidly catalyzed to isovanillic acid by guinea pig liver aldehyde dehydrogenase activity. The inhibitor studies revealed that isovanillin was predominantly metabolized by aldehyde dehydrogenase activity. The oxidation of xenobiotic-derived aromatic aldehydes with freshly prepared or cryopreserved liver slices has not been previously reported. In freshly prepared liver slices, isovanillin was rapidly converted to isovanillic acid, whereas the conversion was very slow in cryopreserved liver slices due to low aldehyde dehydrogenase activity. The formation of isovanillic acid was not altered by allopurinol, but considerably inhibited by disulfiram. It is therefore concluded that isovanillin is predominantly metabolized by aldehyde dehydrogenase activity, with minimal contribution from either aldehyde oxidase or xanthine oxidase. 相似文献
3.
Aristidis S Veskoukis Demetrios Kouretas Georgios I Panoutsopoulos 《European journal of drug metabolism and pharmacokinetics》2006,31(1):11-16
Both aldehyde oxidase and xanthine oxidase catalyze the oxidation of a wide range of N-heterocycles and aldehydes. These enzymes are important in the oxidation of N-heterocyclic xenobiotics, whereas their role in the oxidation of xenobiotic aldehydes is usually ignored. The present investigation describes the interaction of methyl- and nitrosubstituted benzaldehydes, in the ortho-, meta- and parapositions, with guinea pig liver aldehyde oxidase and bovine milk xanthine oxidase. The kinetic constants showed that most substituted benzaldehydes are excellent substrates of aldehyde oxidase with lower affinities for xanthine oxidase. Low Km values for aldehyde oxidase were observed with most benzaldehydes tested, with 3-nitrobenzaldehyde having the lowest Km value and 3-methylbenzaldehyde being the best substrate in terms of substrate efficiency (Ks). Additionally, low Km values for xanthine oxidase were found with most benzaldehydes tested. However, all benzaldehydes also had low Vmax values, which made them poor substrates of xanthine oxidase. It is therefore possible that aldehyde oxidase may be critical in the oxidation of xenobiotic and endobiotic derived aldehydes and its role in such reactions should not be ignored. 相似文献
4.
The biotransformation of halothane was studied using liver slices. Precision-cut Hartley male guinea pig liver slices (1 cm diameter; 250-300 microns thick) were incubated in sealed roller vials containing supplemented Krebs-Henseleit buffer at 37 degrees C under different O2 tensions (2.5, 21, and 95%). After a 1-hr preincubation, halothane was vaporized in the vial producing a 1.9 mM medium concentration. Halothane metabolites (Br-, trifluoroacetic acid, F-) were measured at 2, 4, and 6 hr. Viability of the incubated slices was verified by determining intracellular K+ content and levels of cytochrome P-450, which were maintained under 95% O2 atmosphere but decreased with lower O2 tensions (2.5%). The highest fluoride production was 300 +/- 22 pmol/mg slice weight/6 hr at low O2 tension (2.5%). Defluorination decreased with increasing O2 tension to undetectable levels under 95% O2. Production of the oxidative metabolite, trifluoroacetic acid, was highest at 95% O2 (2.35 +/- 0.17 nmol/mg slice weight/6 hr). Trifluoroacetic acid production decreased with decreasing O2 tension. Br- production was the highest at 21% O2 (1.8 +/- 0.13 nmol/mg slice weight/6 hr). Production of Br- was not dependent on the O2 tension. The guinea pig slices are capable of biotransforming halothane (oxidative/reductive); therefore, this in vitro system appears suitable for studying the biotransformation of halothane. 相似文献
5.
C Stubley J G Stell D W Mathieson 《Xenobiotica; the fate of foreign compounds in biological systems》1979,9(8):475-484
1. Isoquinoline, cinnoline, quinoxaline, quinazoline and phthalazine were incubated with preparations of rabbit liver aldehyde oxidase. 2. The oxidation products, 1-hydroxyisoquinoline, 4-hydroxycinnoline, 2-hydroxy- and 2,3-dihydroxy-quinoxaline, 4-hydroxy- and 2,4-dihydroxy-quinazoline, and 1-hydroxyphthalazine were identified by comparison of their spectral and chromatographic characteristics with those of authentic compounds. 3. Michaelis-Menten constants are reported for the action of the parent heterocycles with aldehyde oxidase. The compounds reported in this study are among the most efficient substrates yet described for rabbit liver aldehyde oxidase. 4. The compounds in 1 above were incubated with bovine milk xanthine oxidase: only quinazoline and phthalazine yielded significant amounts of metabolites. Km values were calculated for these compounds. 5. Incubation of the heterocycles with rat liver preparations gave qualitatively the same results as those obtained using rabbit liver, but smaller amounts of the oxidation products were detected from rat liver incubations. 相似文献
6.
T Biegański W A Fogel Z Korsak C Ma?liński Z Osińska M A Ulatowska 《Polish journal of pharmacology and pharmacy》1984,36(6):633-640
The in vitro influence of ethanol and acetaldehyde on diamine oxidase catalyzed reaction was measured with guinea pig liver and intestine. Acetaldehyde, having no influence on diamine oxidase activity, diminished the formation of gamma-aminobutyric acid or imidazole-4-acetic acid when putrescine or histamine were used, respectively, as enzyme substrate. During ethanol ingestion by guinea pig the enhancement of hepatic diamine oxidase activity was observed after 10 days of treatment with subsequent decrease to the control value on the 18th day. The metabolic products of putrescine in diamine oxidase catalyzed reaction by livers of alcohol animals show similar increase and the same time course as enzymic activity. The per cent distribution of particular products in diamine oxidase reaction was not affected by ethanol administration. 相似文献
7.
To evaluate the metabolic capacity of intact guinea pig liver under normoxic and hypoxic conditions, oxidative and reductive metabolism of diphenyl sulfoxide (DPSO) was studied by the nonrecirculating perfusion method in situ. DPSO was exclusively converted into diphenyl sulfone (DPSO2), an oxidative metabolite, under normoxia. When diphenyl sulfide (DPS) was infused, DPSO was eliminated as a predominant metabolite. Judging from the susceptibility toward selective inhibitors of cytochrome P-450, both oxidative steps appear to be catalyzed by cytochrome P-450-dependent monooxygenase rather than flavin adenine dinucleotide-containing monooxygenase. Under hypoxic conditions, however, DPSO2 formation was decreased in parallel with reduced oxygen concentration in the influent perfusate, whereas only a trace amount of DPS, a reductive metabolite, was detected. On the other hand, coinfusion of an electron donor for aldehyde oxidase such as 2-hydroxypyrimidine and benzaldehyde, but not xanthine, markedly stimulated the formation of DPS during hypoxia. These results indicate that the oxidative pathway catalyzed by cytochrome P-450-dependent monooxygenase is predominant in DPSO metabolism under normoxic conditions, whereas only under hypoxia does the reductive pathway become the major one if an electron donor for aldehyde oxidase exists in intact guinea pig liver. 相似文献
8.
Georgios I Panoutsopoulos Demetrios Kouretas Elias G Gounaris Christine Beedham 《European journal of drug metabolism and pharmacokinetics》2004,29(2):111-118
2-Phenylethylamine is an endogenous constituent of human brain and is implicated in cerebral transmission. It is also found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. Metabolism of 2-phenylethylamine to phenylacetaldehyde is catalyzed by monoamine oxidase and the oxidation of the reactive aldehyde to its acid derivative is catalyzed mainly by aldehyde dehydrogenase and perhaps aldehyde oxidase, with xanthine oxidase having minimal transformation. The present investigation examines the metabolism of 2-phenylethylamine to phenylacetaldehyde in liver slices and compares the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase activity in the oxidation of phenylacetaldehyde with precision-cut fresh liver slices in the presence/absence of specific inhibitors of each enzyme. In liver slices, phenylacetaldehyde was rapidly converted to phenylacetic acid. Phenylacetic acid was the main metabolite of 2-phenylethylamine, via the intermediate phenylacetaldehyde. Phenylacetic acid formation was completely inhibited by disulfiram (specific inhibitor of aldehyde dehydrogenase), whereas isovanillin (specific inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (specific inhibitor of xanthine oxidase) had little or no effect. Therefore, in liver slices, phenylacetaldehyde is rapidly oxidized by aldehyde dehydrogenase and aldehyde oxidase with little or no contribution from xanthine oxidase. 相似文献
9.
Human liver aldehyde oxidase: inhibition by 239 drugs 总被引:1,自引:0,他引:1
The authors tested 239 frequently used drugs and other compounds for their potential to inhibit the drug-metabolizing enzyme, aldehyde oxidase, in human liver cytosol. A sensitive, moderate throughput HPLC-MS assay was developed for 1-phthalazinone, the aldehyde oxidase-catalyzed product of phthalazine oxidation. Inhibition of this activity was examined for the 239 drugs and other compounds of interest at a test concentration of 50 microM. Thirty-six compounds exhibited greater than 80% inhibition and were further examined for measurement of IC50. The most potent inhibitor observed was the selective estrogen receptor modulator, raloxifene (IC50=2.9 nM), and tamoxifen, estradiol, and ethinyl estradiol were also potent inhibitors. Other classes of drugs that demonstrated inhibition of aldehyde oxidase included phenothiazines, tricyclic antidepressants, tricyclic atypical antipsychotic agents, and dihydropyridine calcium channel blockers, along with some other drugs, including loratadine, cyclobenzaprine, amodiaquine, maprotiline, ondansetron, propafenone, domperidone, quinacrine, ketoconazole, verapamil, tacrine, and salmeterol. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which aldehyde oxidase is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme. 相似文献
10.
Aliphatic aldehydes have a high affinity toward aldehyde dehydrogenase activity but are relatively poor substrates of aldehyde oxidase and xanthine oxidase. In addition, the oxidation of xenobiotic-derived aromatic aldehydes by the latter enzymes has not been studied to any great extent. The present investigation compares the relative contribution of aldehyde dehydrogenase, aldehyde oxidase, and xanthine oxidase activities in the oxidation of substituted benzaldehydes in separate preparations. The incubation of vanillin, isovanillin, and protocatechuic aldehyde with either guinea pig liver aldehyde oxidase, bovine milk xanthine oxidase, or guinea pig liver aldehyde dehydrogenase demonstrated that the three aldehyde oxidizing enzymes had a complementary substrate specificity. Incubations were also performed with specific inhibitors of each enzyme (isovanillin for aldehyde oxidase, allopurinol for xanthine oxidase, and disulfiram for aldehyde dehydrogenase) to determine the relative contribution of each enzyme in the oxidation of these aldehydes. Under these conditions, vanillin was rapidly oxidized by aldehyde oxidase, isovanillin was predominantly metabolized by aldehyde dehydrogenase activity, and protocatechuic aldehyde was slowly oxidized, possibly by all three enzymes. Thus, aldehyde oxidase activity may be a significant factor in the oxidation of aromatic aldehydes generated from amines and alkyl benzenes during drug metabolism. In addition, this enzyme may also have a role in the catabolism of biogenic amines such as dopamine and noradrenaline where 3-methoxyphenylacetic acids are major metabolites. 相似文献
11.
Both the plasma membrane-rich fraction and specific granule-rich fraction prepared from human neutrophil lysate by Percoll centrifugation have been reported to contain cytochrome b558, a membrane activation factor for NADPH oxidase. In this study, the plasma membrane-rich fraction and specific granule-rich fraction of guinea pig neutrophils were prepared, and the abilities of both fractions to activate NADPH oxidase in a cell-free system consisting of either fraction, cytosol and arachidonate were compared. There was no difference in the Km value for NADPH between NADPH oxidase activated by specific granules or by plasma membranes. Optimum concentrations of arachidonate for the activation of NADPH oxidase in both the fractions were also the same. However, after freeze-thawing, the specific granules markedly lost the ability, compared to plasma membranes. Such instability of specific granules was also observed on hypotonic- or deoxycholate-treatment. The inactivation by freeze-thawing was not suppressed by proteinase inhibitors, and gp91-phox, a large subunit of cytochrome b558, was not degraded by freeze-thawing. Freeze-thawed specific granules did not affect the ability in plasma membranes, indicating the absence of an inactivating factor in specific granules. The increase in the amount of cytosol in the cell-free assay mixture did not compensate for the markedly decreased ability of freeze-thawed specific granules. Translocation of p47-phox, one of the cytosolic activation factors, to specific granules was not affected by freeze-thawing. We found that the ability of specific granules to activate NADPH oxidase was fragile, though it is unclear what is responsible for the instability, at present. 相似文献
12.
In spite of over 40 years of clinical use of 6-mercaptopurine, many aspects of complex pharmacology and metabolism of this drug remain unclear. It is thought that 6-mercaptopurine is oxidized to 6-thiouric acid through 6-thioxanthine or 8-oxo-6-mercaptopurine by one of two molybdenum hydroxylases, xanthine oxidase (XO), however, the role of other molybdenum hydroxylase, aldehyde oxidase (AO), in the oxidation of 6-mercaptopurine and possible interactions of AO substrates and inhibitors has not been investigated in more details. In the present study, the role of AO and XO in the oxidation of 6- mercaptopurine has been investigated. 6-mercaptopurine was incubated with bovine milk xanthine oxidase or partially purified guinea pig liver molybdenum hydroxylase fractions in the absence and presence of XO and AO inhibitor/substrates, and the reactions were monitored by spectrophotometric and HPLC methods. According to the results obtained from the inhibition studies, it is more likely that 6- mercaptopurine is oxidized to 6-thiouric acid via 6-thioxanthine rather than 8-oxo-6-mercaptopurine. The first step which is the rate limiting step is catalyzed solely by XO, whereas both XO and AO are involved in the oxidation of 6-thioxanthine to 6-thiouric acid. 相似文献
13.
Manfred Kiese Gerhard Renner Ingrid Wiedemann 《Naunyn-Schmiedeberg's archives of pharmacology》1966,252(5):418-423
Summary N-hydroxy-2-aminofluorene was found in the urine of guinea pigs intraperitoneally injected with 2-aminofluorene. The hydroxylamine was oxidized to the nitroso analogue and this was identified and determined in the carbon tetrachloride extract by its characteristic UV absorption, by thin-layer chromatography, and by the formation of a diazo compound in the reaction with nitrous acid. Only a small fraction of the 2-aminofluorene injected appeared in the urine as N-hydroxy derivative.Guinea pig liver microsomes were observed to N-hydroxylate 2-aminofluorene rather rapidly, the reaction proceeding at least as rapidly as the N-hydroxylation of aniline.The results of this paper were presented at meetings of the Deutsche Pharmakologische Gesellschaft in Mainz, April 26 to 28, 1965 (Kampffmeyer and Kiese) and Göttingen, September 27 to 30, 1965 (von Jagow, Kiese, Renner, and Wiedemann). 相似文献
14.
Maryam Hamzeh-Mivehroud Seifullah Rahmani Mohammad-Reza Rashidi Siavoush Dastmalchi 《Medicinal chemistry research》2016,25(12):2773-2786
In this study, guinea pig aldehyde oxidase inhibitory activities of flavonoids were investigated using in silico, quantitative structure–activity relationships, molecular modeling, and experimental techniques, in order to understand more about their mode of interactions. The aldehyde oxidase inhibitory activity values determined experimentally in this work or collected from our previous report were used to derive mathematical models for the prediction purposes employing combined genetic algorithm and partial least square method, as well as multiple linear regression analysis. The statistical parameters for the developed models and the results of leave-one-out internal cross-validation were indicative of the validity of the models. To further investigate the mechanism of interaction between flavonoid inhibitors and guinea pig aldehyde oxidase enzyme, the structural model of the enzyme was built and the inhibitors were docked manually into the binding site. The model for quercetin-aldehyde oxidase complex was validated based on its appropriate stability during 10?ns molecular dynamics simulation, and hence the positioning procedure for the rest of flavonoids was guided based on the manually docked position of quercetin. The identified interactions were compared with those of flavonoids previously reported for rat aldehyde oxidase and the results showed a substantial commonality between the modes of interactions predicted for flavonoids positioned into the binding site of aldehyde oxidase from guinea pig and rat. This commonality is also reflected by the quantitative structure–activity relationships models. The results presented in this work may provide useful information where the structural requirements for aldehyde oxidase inhibition are sought, such as designing novel aldehyde oxidase inhibitors or investigating drug interaction involving aldehyde oxidase mediated biotransformation. 相似文献
15.
Cinchona alkaloids (quinine, quinidine, cinchonine, and cinchonidine) were incubated with partially purified aldehyde oxidase from rabbit or guinea pig liver. Reversed-phase HPLC methods were developed to separate the oxidation products from the parent drugs, and the metabolites were identified on the basis of their infrared and mass spectral characteristics. All four alkaloids were oxidized at carbon 2 of the quinoline ring to give the corresponding lactams. In addition, the dihydro contaminants of the cinchona alkaloids were also metabolized by aldehyde oxidase to the 2-quinolone derivatives. Kinetic constants for the oxidation reactions were determined spectrophotometrically and showed that these substrates have a low affinity (KM values of around 10(-5) M) for hepatic aldehyde oxidase, coupled with a relatively low oxidation rate. However, the overall efficiency of the enzyme (Vmax/KM) toward this group of compounds indicates that in vivo biotransformation by aldehyde oxidase will be a significant pathway. Microsomal metabolites were also isolated from quinine and quinidine incubations with rabbit or guinea pig liver fractions. 3-Hydroxyquinine (quinidine) and O-desmethylquinine (quinidine) were identified in microsomal and 10,000g supernatant extracts from quinine and quinidine, respectively. Oxidation of quinine via aldehyde oxidase appeared to be the predominant pathway in rabbit 10,000g fractions, because 2'-quininone was the major metabolite under these conditions with lower concentrations of the microsomal metabolites produced along with a dioxygenated derivative thought to be 3-hydroxy-2'-quininone. 相似文献
16.
Oxidation of selected pteridine derivatives by mamalian liver xanthine oxidase and aldehyde oxidase.
Considerable information is available concerning the oxidation of pteridine derivatives by bovine milk xanthine oxidase, but few investigations have been carried out on the oxidation of such compounds by mammalian liver xanthine oxidase and the related aldehyde oxidase. Xanthine oxidase, obtained from rat liver, oxidizes a variety of substituted amino- and hydroxypteridines in a manner identical to that previously observed for milk xanthine oxidase. For example, 2-aminopteridine and its 4- and 7-hydroxy derivatives were oxidized efficiently to 2-amino-4,7-dihydroxypteridine (isoxanthopterin) by the rat liver enzyme, and 4-aminopteridine and its 2- and 7-hydroxy derivatives were oxidized to 4-amino-2,7-dihydroxypteridine.4-Hydroxypteridine and the isomeric 2- and 7-hydroxypteridines were oxidized by rat liver xanthine oxidase to 2,4,7-trihydroxypteridine. Rabbit liver aldehyde oxidase, but not rat liver xanthine oxidase, was able to catalyze the oxidation in position 7 of 2,4-diaminopteridine and its 6-methyl and 6-hydroxymethyl derivatives. 2-Aminopteridine and 4-aminopteridine were both oxidized to the corresponding 7-hydroxy derivatives in the aldehyde oxidase system; 2-amino-4-hydroxypteridine appeared to be a minor product in the oxidation of 2-aminopteridine by rabbit liver aldehyde oxidase. Both aldehyde oxidase and xanthine oxidase were able to catalyze the oxidation of 2-amino-6,7-disubstituted pteridines to the corresponding 4-hydroxy derivatives; 4-hydroxy-6,7-disubstituted pteridines were oxidized in position 2 by both enzymes. 4-Amino-6,7-disubstituted pteridines were not oxidized by either enzyme. 2-Amino-4-methylpteridine was oxidized in position 7 by aldehyde oxidase but was not an effective substrate for xanthine oxidase; 2-hydroxypteridine and 7-hydroxypteridine were not oxidized to a detectably extent by aldehyde oxidase. All oxidations mediated by xanthine oxidase were strongly inhibited by allopurinol (4-hydroxypyrazolo[3,4-d]pyrimidine), and all oxidations mediated by aldehyde oxidase were inhibited by menadione (2-methyl-1,4-naphthoquinone). Rat liver xanthine oxidase and, to a lesser extent, rabbit liver aldehyde oxidase were inhibited by 4-chloro-6,7-dimethylpteridine; 2-amino-3-pyrazinecarboxylic acid inhibited xanthine oxidase but not aldehyde oxidase. The oxidations of 2- and 4-aminopteridines by aldehyde oxidase resulted in concomitant reduction of cytochrome c. 相似文献
17.
Diamine oxidase activity and imidazoleacetic acid formation in the foetal and maternal guinea pig liver during gestation were examined. DAO activity and IMAA formation in the foetal liver increased continuously, while maternal enzyme activity and ImAA formation in the second half of pregnancy simultaneously decreased. The roles of GABA and ImAA are discussed. 相似文献
18.
Ontogeny of the activity of alcohol dehydrogenase and aldehyde dehydrogenases in the liver and placenta of the guinea pig 总被引:1,自引:0,他引:1
The objectives of this study were to elucidate the ontogeny of the activity of alcohol dehydrogenase (ADH), low Km aldehyde dehydrogenase (ALDH) and high Km ALDH in the liver and placenta of the guinea pig, and to determine the relationship between the relative activity of each enzyme in the guinea pig maternal-placental-fetal unit and the disposition of ethanol and its proximate metabolite, acetaldehyde. The enzyme activities were determined in maternal liver, fetal liver, and placenta of the guinea pig at 34, 50, 60 and 65 days of gestation (term, about 66 days), in the liver of the 2-day-old neonate, and in adult liver. There was low ADH activity in fetal liver and placenta throughout gestation and in neonatal liver. The fetal liver low Km ALDH activity increased progressively and, at 60 days of gestation, was similar to adult liver activity, as was also the case for neonatal liver enzyme activity. Placental low Km ALDH activity was less than adult liver activity throughout gestation. Fetal hepatic high Km ALDH activity increased during gestation, but was less than adult liver activity, as was also the case for neonatal liver enzyme activity. Placental high Km ALDH activity was low throughout gestation. For oral administration of 0.5 g ethanol/kg maternal body weight to pregnant guinea pigs at mid-gestation (34 days), the maternal blood and fetal body ethanol concentration-time curves were similar. Acetaldehyde was measurable in maternal blood and fetal body at similar concentrations, which were 100- to 1000-fold less than the respective ethanol concentrations. The major difference in the disposition of ethanol and acetaldehyde at near-term pregnancy, compared with mid-gestation, was the lack of measurable acetaldehyde in fetal blood. These results indicate that the guinea pig fetus throughout gestation has virtually no capacity to oxidize ethanol, and its duration of exposure to ethanol is regulated by maternal hepatic ADH-catalyzed biotransformation of ethanol. The fetus, however, appears to have increasing low Km ALDH-dependent capacity to oxidize ethanol-derived acetaldehyde during development, and would appear to be increasingly protected from exposure to acetaldehyde as gestation progresses. 相似文献
19.
20.
R Scott Obach 《Drug metabolism and disposition》2004,32(1):89-97
The selective estrogen receptor modulator, raloxifene, has been demonstrated as a potent uncompetitive inhibitor of human liver aldehyde oxidase-catalyzed oxidation of phthalazine, vanillin, and nicotine-Delta1'(5')-iminium ion, with K(i) values of 0.87 to 1.4 nM. Inhibition was not time-dependent. Raloxifene has also been shown to be a noncompetitive inhibitor of an aldehyde oxidase-catalyzed reduction reaction of a hydroxamic acid-containing compound, with a K(i) of 51 nM. However, raloxifene had only small effects on xanthine oxidase, an enzyme related to aldehyde oxidase. In addition, several other compounds of the same therapeutic class as raloxifene were examined for their potential to inhibit aldehyde oxidase. However, none were as potent as raloxifene, since IC(50) values were orders of magnitude higher and ranged from 0.29 to 57 micro M. In an examination of analogs of raloxifene, it was shown that the bisphenol structure with a hydrophobic group on the 3-position of the benzthiophene ring system was the most important element that imparts inhibitory potency. The relevance of these data to the mechanistic understanding of aldehyde oxidase catalysis, as well as to the potential for raloxifene to cause drug interactions with agents for which aldehyde oxidase-mediated metabolism is important, such as zaleplon or famciclovir, is discussed. 相似文献