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PubMed1980

Metabolism of carcinogenic 2-hydroxybenz.

The rates of metabolism of the carcinogenic 2-hydroxybenzo[a]pyrene (2-OH-B[a]P) and the non-carcinogenic 3- and 9-hydroxybenzo[a]pyrenes in cultured cell systems have been studied and compared. While 70-80% of the non-carcinogens are converted to water-soluble derivatives by hamster embryo fibroblasts in 24 h, carcinogenic 2-OH-B[a]P is metabolized at a slower rate (45% in 24 h), comparable to that for the parent hydrocarbon, benzo[a]pyrene (B[a]P). Analysis of extracellular organic solvent-soluble metabolites of 2-OH-B[a]P in cultured hamster embryo fibroblasts, using h.p.l.c., indicates the presence of a single major metabolite, which has been identified by mass spectroscopy as a dihydroxy derivative of B[a]P. At least one additional major organic solvent-soluble metabolite is formed in cultures of either mouse epidermal epithelial cells or human foreskin fibroblasts, indicating a different balance of metabolic pathways in these cell systems. The greater persistence of carcinogenic 2-OH-B[a]P in cells and its higher concentration in the cell cytoplasm compared with the non-carcinogenic phenols may be related to its relatively high biological activity. Differences in metabolism of 2-OH-B[a]P in several cultured cell systems indicate the importance of an appropriate choice of activating system in understanding the relationship between metabolism and carcinogenesis.

Animals↗
PubMed1982

Identification of metabolites of benzo[b]fluoranthene.

The metabolism by rat liver 9000 x g supernatant of the environmental carcinogen benzo[b]fluoranthene was investigated. The major metabolites were identified, by comparison to synthetic samples, as 5- and 6-hydroxybenzo[b]fluoranthene and 4- and 7-hydroxybenzo[b]fluoranthene. The principal dihydrodiol metabolite formed under these conditions was trans-11,12-dihydro-11,12-dihydroxybenzo[b]fluoranthene, which was identified by comparison to the synthetic compound. 1,2-Dihydro-1,2-dihydroxybenzo[b]fluoranthene was identified, by its mass spectrum and by comparison if its u.v. spectrum to that of a synthetic model compound, 11-ethylidene-11H-benzo[b]fluorene. No evidence was obtained for the formation of 7b,8-dihydro-7,8-dihydroxybenzo[b]fluoranthene or trans-9,10-dihydro-9,10-dihydroxybenzo[b]fluoranthene. The latter would be the precursor to a bay region dihydrodiol epoxide of benzo[b]fluoranthene.

Animals↗
PubMed1983

Identification of the metabolites of benzo[f]quinoline and benzo[h]quinoline formed by rat liver homogenate.

Benzo[f]quinoline and benzo[h]quinoline are widespread environmental pollutants which have been found to be mutagenic. The metabolism of benzo[f]quinoline and benzo[h]quinoline was investigated using a liver homogenate from Aroclor-pretreated rats. The metabolites of benzo[f]quinoline which were identified were 7,8-dihydroxy-7,8-dihydrobenzo[f]quinoline, 9,10-dihydroxy-9,10-dihydrobenzo[f]quinoline, 7-hydroxybenzo[f]quinoline, and benzo[f]quinoline-N-oxide. Metabolism studies on benzo[f]quinoline performed in the presence of the epoxide hydratase inhibitor, 3,3,3-trichloropropylene oxide, demonstrated that the formation of both of these dihydrodiols can be inhibited. The major metabolites of benzo[h]quinoline were identified as 5,6-dihydroxy-5,6-dihydrobenzo[h]quinoline and 7,8-dihydroxy-7,8-dihydrobenzo[h]quinoline. Benzo[h]quinoline-N-oxide was not detected as a metabolite. In the presence of an epoxide hydratase inhibitor, the major metabolites of benzo[h]quinoline were 5,6-epoxybenzo[h]quinoline and 7-hydroxybenzo[h]quinoline. The difference in the metabolism to N-oxides observed between benzo[h]quinoline and benzo[f]quinoline is consistent with previous observations in which sterically hindered aromatic ring nitrogen compounds such as benzo[h]quinoline are more resistant to N-oxide formation. The nitrogen atom of these aza-arenes with its lone pair of electrons has a significant influence on sites at which dihydrodiols are formed. The data suggest that the aromatic ring nitrogen of these azaphenanthrenes has an effect similar to that of a methyl substituent in directing their metabolic oxidation.

Animals↗
PubMed1984

Ellagic acid: a potent naturally occurring inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation and covalent binding to DNA in cultured BALB/C mouse keratinocytes.

The metabolism of [3H]benzo[a]pyrene (BP) by cultured primary keratinocytes prepared from BALB/C mouse epidermis was found to be largely inhibited by the dietary plant phenol, ellagic acid. Varying concentrations of ellagic acid added to the keratinocyte cultures resulted in a dose-dependent inhibition of the cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin-O-deethylase (ECD). The major organic solvent-extractable metabolites found intracellularly in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP-7,8-diol) and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of 9-hydroxybenzo[a]pyrene, quinones and trans-9,10-dihydro-9,10-dihydroxybenzo[a]-pyrene (BP-9,10-diol) were also present. The major organic solvent-extractable metabolites found in the extracellular culture medium were BP-7,8-diol and BP-9,10-diol, with smaller quantities of unconjugated phenols and quinones. The major intracellular and extracellular water-soluble metabolites of BP were conjugated with glucuronide (primarily 3-OH-BP and several BP-quinones), and to a lesser extent with sulfate (primarily BP-7,8-diol). Both intracellular and extracellular metabolism of organic solvent-extractable and water-soluble conjugates was significantly inhibited by ellagic acid in a dose-dependent manner. The intracellular enzyme-mediated binding of BP to mouse keratinocyte DNA was also largely inhibited in a dose-dependent fashion by ellagic acid. Our results indicate that cultured primary mouse keratinocytes offer a useful model system for studying factors affecting the metabolic activation and detoxification of polycyclic aromatic hydrocarbon carcinogens in the epidermis, and that polyphenolic compounds such as ellagic acid may prove useful in modulating the risk of cutaneous cancer that results from exposure to these environmental chemicals.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2003

Microbial aromatic acid metabolites formed in the gut account for a major fraction of the polyphenols excreted in urine of rats fed red wine polyphenols.

The health effects of dietary polyphenols might be explained by both intact compounds and their metabolites formed either in the tissues or in the colon by the microflora. The quantitative importance and biological activities of the microbial metabolites have seldom been examined in vivo. We measured the microbial metabolites formed in four groups of rats (n = 8) fed for 8 d a diet supplemented with 0.12 g/100 g catechin, 0.25 or 0.50 g/100 g red wine powder containing proanthocyanidins, phenolic acids, flavanols, anthocyanins and flavonols or an unsupplemented diet. Fourteen aromatic acid metabolites were assayed in urine collected for 24 h by an HPLC-electrospray ionization (ESI)-mass spectrometry (MS)-MS method. The three main metabolites formed from the catechin diet were 3-hydroxyphenylpropionic acid, 3-hydroxybenzoic acid and 3-hydroxyhippuric acid. Their total urinary excretion accounted for 4.7 g/100 g of the catechin ingested and that of intact catechins for 45.3 g/100 g. For wine polyphenols, the same microbial metabolites as observed for the catechin diet were identified in urine along with hippuric, p-coumaric, vanillic, 4-hydroxybenzoic and 3-hydroxyphenylacetic acids. All together, these aromatic acids accounted for 9.2 g/100 g of the total wine polyphenols ingested and intact catechins for only 1.2 g/100 g. The higher excretion of aromatic acids by rats fed wine polyphenols is likely due to their poor absorption in the proximal part of the gut. Some of the microbial metabolites still bear a reducing phenolic group and should also prevent oxidative stress in inner tissues. More attention should be given in the future to these microbial metabolites and their biological properties to help explain the health effects of polyphenols that are not easily absorbed through the gut barrier.

Animals↗
PubMed1978

Effects of administration to mice of butylated hydroxyanisole by oral intubation on benzo[a]pyrene-induced pulmonary adenoma formation and metabolism of benzo[a]pyrene.

Administration of butylated hydroxyanisole (BHA) by oral intubation 4 hours before challenge with benzo[a]pyrene (BP) inhibited the formation of pulmonary adenomas in A/HeJ mice. Incubation of BP with liver microsomes from mice that received BHA 2,4, or 8 hours before being killed resulted in less binding of BP metabolites to added DNA than occurred with control microsomes. High-pressure liquid chromatography studies of the BP metabolite pattern produced by the incubation of BP with liver microsomes from mice given BHA by oral intubation showed a decrease in formation of BP-4,5-oxide and 9-hydroxybenzo[a]pyrene. In contrast, the formation of 3-hydroxybenzo[a]-pyrene was increased. The was increased. The short interval between the administration of BHA by oral intubation and the observed biochemical changes indicated that BHA could exert a direct effect on the microsomal metabolism of BP. These changes in metabolism of BP occurred under conditions of BHA administration that produced a decreased neoplastic response to this carcinogen.

Adenoma↗
PubMed1998

Expression of bacterial chorismate pyruvate-lyase in tobacco: evidence for the presence of chorismate in the plant cytosol.

The bacterial gene ubiC encodes chorismate pyruvate-lyase, an enzyme which converts chorismate to 4-hydroxybenzoate and which is not normally present in plants. The UbiC protein was expressed in tobacco, with targeting of the gene product either to the plastids or to the cytosol. In both cases, chorismate pyruvate-lyase activity and a resulting formation of 4-hydroxybenzoate was detected. This suggests that chorismate, a metabolite of the shikimate pathway, is present not only in the plastids but also in the cytosol of plant cells.

Agrobacterium tumefaciens↗
PubMed2000

Genetic engineering on shikonin biosynthesis: expression of the bacterial ubiA gene in Lithospermum erythrorhizon.

The naphthoquinone pigment shikonin from Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae) was the first plant secondary metabolite produced in industrial scale from plant cell cultures. We have now manipulated the biosynthetic pathway leading to shikonin in L. erythrorhizon by introduction of the bacterial gene ubiA. This gene of Escherichia coli encodes 4-hydroxybenzoate-3-polyprenyltransferase, a membrane-bound enzyme that catalyzes a key step in ubiquinone biosynthesis. Using geranyl diphosphate (GPP) as substrate, it is able to catalyze the formation of 3-geranyl-4-hydroxybenzoate (GBA), a principal step of shikonin biosynthesis. The prokaryotic ubiA gene was fused to two signal sequences for targeting of the resulting peptide to the endoplasmic reticulum (ER). Constructs with different constitutive promoters were introduced into L. erythrorhizon using Agrobacterium rhizogenes-mediated transformation. In the resulting hairy root lines, high UbiA enzyme activities could be observed, reaching 133 pkat mg(-1). Expression of ubiA resulted in an accumulation of GBA in an amount exceeding that of the control culture by a factor of 50. However, the ubiA-transformed lines showed only a marginal (average 22%) increase of shikonin production in comparison to the control lines, and there was no significant correlation of UbiA enzyme activity and shikonin accumulation. This suggests that overexpression of ubiA alone is not sufficient to increase shikonin formation, and that further enzymes are involved in the regulation of this pathway.

Alkyl and Aryl Transferases↗
PubMed2002

High level expression of chorismate pyruvate-lyase (UbiC) and HMG-CoA reductase in hairy root cultures of Lithospermum erythrorhizon.

Shikonin, a red naphthoquinone pigment, is produced by cell cultures of Lithospermum erythrorhizon (Boraginaceae). It is biosynthetically derived from two key precursors, 4-hydroxybenzoate (4HB) and geranyldiphosphate (GPP). The bacterial ubiC gene, encoding chorismate pyruvate-lyase (CPL) which converts chorismate to 4-hydroxybenzoate, was expressed in L. erythrorhizon under the control of the strong (ocs)(3)mas-promoter. This introduced an efficient biosynthetic pathway to 4HB, i.e. a one-step reaction from chorismate, in addition to the endogeneous multi-step phenylpropanoid pathway. Feeding experiments with [1,7-(13)C(2)]shikimic acid showed that in the most active transgenic line, 73% of 4HB was synthesized via the genetically introduced pathway. However, there was no correlation between CPL activity and 4HB glucoside or shikonin accumulation in the transgenic lines. HMG-CoA reductase (HMGR) is involved in the biosynthesis of GPP in L. erythrorhizon. Two forms of HMGR1 of Arabidopsis thaliana were expressed in Lithospermum under control of the (ocs)(3)mas promoter. Only moderate increases in enzyme activity were obtained with the complete enzyme, but high activity was achieved using the soluble cytosolic domain of HMGR1. Shikonin accumulation remained unchanged even upon high expression of soluble HMGR.

Arabidopsis↗
PubMed2000

Description of strain 3CB-1, a genomovar of Thauera aromatica, capable of degrading 3-chlorobenzoate coupled to nitrate reduction.

A Gram-negative bacterium, strain 3CB-1, isolated from a 3-chlorobenzoate enrichment culture inoculated with a sediment sample is capable of degrading various aromatic compounds and halogenated derivatives with nitrate as electron acceptor. Compounds capable of serving as carbon and energy sources include 3-chlorobenzoate, 3-bromobenzoate, 2-fluorobenzoate, 4-fluorobenzoate, benzoate, 3-hydroxybenzoate, 4-hydroxybenzoate, 3-aminobenzoate, protocatechuate, m-cresol and p-cresol. Oxygen, nitrate and nitrite were used as electron acceptors for growth. Cells are Gram-negative short rods with peritrichous flagellation. The predominant fatty acids are cis-9-hexadecenoic acid (16:1 omega 7c), hexadecanoic acid (16:0), octadecanoic acid (18:0), octadecenoic acid (18:1), 3-hydroxydecanoic acid (10:0 3OH) and dodecanoic acid (12:0). The sequence of the 16S rRNA gene, as well as the fatty acid composition, indicate that the strain is a member of the genus Thauera in the beta-subclass of the Proteobacteria and very close to Thauera aromatica. DNA-DNA hybridization and nutrient screening indicate that strain 3CB-1 is a genomovar of Thauera aromatica with the proposed name Thauera aromatica genomovar chlorobenzoica.

Biodegradation, Environmental↗
PubMed1992

Novel degradative pathway of 4-nitrobenzoate in Comamonas acidovorans NBA-10.

A Comamonas acidovorans strain, designated NBA-10, was isolated on 4-nitrobenzoate as sole carbon and energy source. When grown on 4-nitrobenzoate, it was simultaneously adapted to 4-nitrosobenzoate and 4-hydroxylaminobenzoate but not to 4-hydroxybenzoate or 4-aminobenzoate. In cell extracts with NADPH present, 4-nitrobenzoate was degraded to 4-hydroxylaminobenzoate and 3,4-dihydroxybenzoate. Partial purification of the 4-nitrobenzoate reductase revealed that 4-nitrobenzoate is degraded via 4-nitrosobenzoate to 4-hydroxylamino-benzoate. The substrate specificity of the enzyme was narrow and NADPH was 15 times more effective as a cofactor than NADH. The results provide evidence for a novel pathway for aerobic degradation of 4-nitrobenzoate, since neither 4-hydroxybenzoate nor 4-aminobenzoate were involved in the degradative pathway.

Kinetics↗
PubMed1997

Tissue-Specific and Development-Dependent Accumulation of Phenylpropanoids in Larch Mycorrhizas.

The tissue-specific and development-dependent accumulation of secondary products in roots and mycorrhizas of larch (Larix decidua Mill.; Pinaceae) was studied using high-performance liquid chromatography and histochemical methods. The compounds identified were soluble catechin, epicatechin, quercetin 3-O-[alpha]-rhamnoside, cyanidin- and peonidin 3-O-[beta]-glucoside, 4-O-[beta]-hydroxybenzoyl-O-[beta]-glucose, 4-hydroxybenzoate 4-O-[beta]-glucoside, maltol 3-O-[beta]-glucoside, and the wall-bound 4-hydroxybenzaldehyde, vanillin, and ferulate. In addition, we partially identified a tetrahydroxystilbene monoglycoside, a quercetin glycoside, and eight oligomeric proanthocyanidins. Comparison between the compounds accumulating in the apical tissue of fine roots, long roots, and in vitro grown mycorrhizas (L. decidua-Suillus tridentinus) showed elevated levels of the major compounds catechin and epicatechin as well as the minor compound 4-hydroxybenzoate 4-O-[beta]-glucoside specifically in the root apex of young mycorrhizas. The amounts of wall-bound 4-hydroxybenzaldehyde and vanillin were increased in all of the mycorrhizal sections examined. During the early stages of mycorrhization the concentrations of these compounds increased rapidly, perhaps induced by the mycorrhizal fungus. In addition, studies of L. decidua-Boletinus cavipes mycorrhizas from a natural stand showed that the central part of the subapical cortex tissue and the endodermis both accumulate massive concentrations of catechin, epicatechin, and wall-bound ferulate compared with the outer part of the cortex, where the Hartig net is being formed.

Journal Article↗
PubMed1973

Influence of phenolic acids on ion uptake: I. Inhibition of phosphate uptake.

The influence of naturally occurring phenolic acids on phosphate uptake by barley (Hordeum vulgare L. cv. Karlsberg) roots was examined using (32)P-labeled phosphate. Without exception, all compounds tested, namely, benzoic, 2-hydroxybenzoic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,4,5-trihydroxybenzoic, 4-hydroxy-3-methoxybenzoic, 4-hydroxy-3,5-dimethoxybenzoic, cinnamic, 2-hydroxycinnamic, 4-hydroxycinnamic, 3,4-dihydroxycinnamic, 4-hydroxy-3-methoxycinnamic, and 4-hydroxy-3,5-dimethoxycinnamic acids, inhibited uptake.The degree of inhibition correlated well with the lipid solubility of these phenolic compounds. This as well as kinetic data support the hypothesis of inhibition through altered membrane properties.

Journal Article↗
PubMed2004

Adducts of 1,4,8,11-tetraazacyclotetradecane with carboxylic acids: hydrogen-bonded supramolecular structures in two or three dimensions.

Four solvated salt-type adducts derived from cyclam (1,4,8,11-tetraazacyclotetradecane) and carboxylic acids have been structurally characterized. In the salt derived from adamantane-1-carboxylic acid, 4,11-diaza-1,8-diazoniacyclotetradecane bis(adamantane-1-carboxylate) tetrahydrate, (1) (monoclinic, P2(1)/c, Z' = 0.5), where the cation lies across a centre of inversion, the anions and the water molecules form chains of edge-fused R(4)(2)(8) and R(6)(6)(16) rings, which are linked into sheets by the cations. In the 4-aminobenzoate salt, 4,11-diaza-1,8-diazoniacyclotetradecane bis(4-aminobenzoate) monohydrate, (2) (monoclinic, C2/c, Z' = 0.5), where the cation lies across a centre of inversion and the water molecule lies across a twofold rotation axis, the cations and anions generate a three-dimensional framework, readily analysed in terms of two distinct two-dimensional substructures, viz. (10;1) sheets of R(8)(6)(46) rings, and pairwise interwoven (100) sheets, reinforced by water molecules. The 3-hydroxybenzoate salt, 4,11-diaza-1,8-diazoniacyclotetradecane bis(3-hydroxybenzoate) dihydrate, (3) (monoclinic, Pc, Z' = 1), contains a three-dimensional framework constructed from anions and water molecules only, which encapsulates large voids and within which the cations are linked to the anion-water framework via N-H.O hydrogen bonds. There are two independent cations in 4,11-diaza-1,8-diazoniacyclotetradecane 5-hydroxyisophthalate(2-) methanol solvate, (4) (monoclinic, P2(1)/c, Z' = 1), both lying across centres of inversion but with entirely different configurations. The anions alone form simple chains, and these chains are linked by the two types of cation into a three-dimensional framework from which the methanol molecules are pendent. Comparisons are made with carboxylate complexes of the [Ni(cyclam)](2+) cation and with carboxylate salts derived from meso-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane.

Journal Article↗
PubMed1986

Clotrimazole, an inhibitor of benzo[a]pyrene metabolism and its subsequent glucuronidation, sulfation, and macromolecular binding in BALB/c mouse cultured keratinocytes.

The effect of the antifungal imidazole compound, clotrimazole, on the metabolism of benzo[a]pyrene (BP) was studied in cultured keratinocytes prepared from BALB/c mouse epidermis. Varying concentrations of clotrimazole added to the cultured keratinocytes resulted in a dose-dependent inhibition of the activities of the microsomal cytochrome P-450-dependent monooxygenases aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The major organic solvent-soluble metabolites of BP identified in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol), 9-hydroxybenzo[a]pyrene (9-OH-BP), and 3-hydroxybenzo[a]pyrene (3-OH-BP), although small amounts of trans-4,5-dihydro-4,5-dihydroxybenzo[a]pyrene, BP-quinones, and trans-9,10-dihydroxybenzo[a]pyrene were also present. The major organic solvent-extractable metabolites of BP found in the extracellular culture medium were primarily the diols with smaller quantities of phenols and quinones. The major water-soluble metabolites of BP present both intracellularly and extracellularly were glucuronide conjugates of 3-OH-BP, 9-OH-BP, and benzo[a]pyrene-3,6-dione and to a lesser extent sulfate conjugates (primarily of the BP-7,8-diol). Clotrimazole inhibited the generation of organic solvent-soluble and water-soluble conjugates in a dose-dependent manner. The in vitro metabolism of BP by microsomes prepared from control and benz[a]anthracene (BA)-induced cultured keratinocytes was also inhibited by clotrimazole with greater inhibitory effect on BA-induced keratinocytes especially with respect to the formation of diols and quinones. The enzyme-mediated covalent binding of BP to mouse keratinocyte DNA and protein was also substantially diminished by clotrimazole in a dose-dependent fashion. These results indicate that clotrimazole, a widely used drug for the management of a variety of superficial dermatophyte infections of the skin, is a potent inhibitor of cytochrome P-450-dependent transformation of polycyclic aromatic hydrocarbons in cultured murine keratinocytes. This system offers a convenient approach for studies as inhibitors of carcinogen metabolism in the epidermis.

Animals↗
PubMed1989

Substrate-modulated reactions of putidamonooxin. The nature of the active oxygen species formed and its reaction mechanism.

1. 4-Methoxybenzoate monooxygenase is fairly nonspecific. The enzyme system with putidamonooxin as its oxygen-activating component catalyses: (a) O-, S- and N-demethylation; (b) the oxygenation of 4-methylbenzoate and 4-methylmercaptobenzoate, with formation of 4-carboxybenzyl alcohol and 4-carboxyphenylmethyl sulfoxide, respectively, and (c) attack of the aromatic ring of 4- and 3-hydroxybenzoate and 4-aminobenzoate, yielding 3,4-dihydroxybenzoate and 4-amino-3-hydroxybenzoate, respectively. 2. Compounds which are bound by the active sites of putidamonooxin have two essential features in common: a planar aromatic ring system, and a free carboxyl group attached to it. 3. By a substrate-modulated reaction putidamonooxin can be induced to function not only as a monooxygenase but also as a peroxotransferase, i.e. it incorporates both atoms of the activated oxygen molecule into a substrate molecule. This finding supports the hypothesis that a mesomeric state of the iron.peroxo complex, [FeO2]+, is indeed the active oxygenating species of putidamonooxin. 4. The lifetime of the ternary complex consisting of enzyme.iron-peroxo-complex.substrate is significantly prolonged by uncoupling and partially uncoupling substrates, except when it is inactivated by protonation of the iron.peroxo complex by a proton transported into the active sites by a special kind of substrate (i.e. isomers of monoaminobenzoate), with the direct formation of H2O2. 5. The lifetime of the active oxygen species is determined by (a) the rate of the oxygenation reaction in the presence of tight-coupling substrates and (b) the rate of the oxygenation reaction as well as detoxification by the availability of a dissociable proton in the presence of partial uncoupling (and uncoupling) substrate analogues. 6. The rate of the oxygenation reaction depends on the lifetime of the active oxygen species, [FeO2]+, in the presence of partial uncoupling substrates. 7. The iron.peroxo complex attacks an aromatic ring system according to the empiric rules of electrophilic substitution, whereas the attack of aliphatic substituents at the aromatic ring is controlled by steric criteria.

Benzoates↗
PubMedDate not supplied

Pneumocystis carinii f. sp. carinii synthesizes de novo four homologs of ubiquinone.

Ubiquinone, coenzyme Q, plays a pivotal role in electron transport and is a target for chemotherapy against a number of eukaryotic infectious agents, including Pneumocystis carinii. Coenzyme Q10 was previously identified as the major ubiquinone homolog in P. carinii isolated and purified from rat lungs; CoQ9 was also present. In contrast, CoQ9 and CoQ8 (but not CoQ10) were detected in the lungs of uninfected rat controls. These observations suggested that the pathogen synthesizes CoQ10, and perhaps CoQ9 as well. In the present study, CoQ biosynthesis in P. carinii was examined in greater detail. Radiolabeled mevalonate, a precursor of the CoQ polyprenyl chain, was incorporated in vitro into P. carinii ubiquinones. Incorporation of radiolabeled mevalonate into P. carinii CoQ was not enhanced by treating cells with lovastatin, suggesting that the cells did not transport the drug, or that a lovastatin-insensitive pathway for de novo synthesis of isoprenoids may also function in this organism. Radiolabeled precursors of the ring moiety, including shikimic acid, p-hydroxybenzoic acid, and tyrosine were also incorporated into P. carinii CoQ. Unexpectedly, it was found that not only CoQ9 and CoQ10, but also CoQ7, and CoQ8, were metabolically radiolabeled by all the precursors tested, indicating that the organism synthesizes CoQ7, CoQ8, CoQ9, and CoQ10. Metabolic radiolabeling of ubiquinones in rat lung controls was not detected in experiments using either radioactive mevalonate or p-hydroxybenzoate. Thus the incorporations measured using purified P. carinii preparations were due to the enzymes of the organism.

Animals↗
PubMed1986

Does naloxone induce relaxation of guinea-pig airway smooth muscle?

The effects of the opiate receptor antagonist naloxone were investigated on isolated preparations of guinea-pig trachealis contracted with either histamine, methacholine or KCl. The commercially available solution of naloxone (Narcan) induced concentration-dependent relaxation of the contracted airway preparations. In stark contrast, aqueous solutions of naloxone were without any significant relaxant effect. Aqueous solutions of the preservatives (methyl and propyl hydroxybenzoate) present in the vehicle used in the commercial formulation of naloxone mimicked exactly the relaxant effects induced by Narcan. Thus, naloxone does not directly induce relaxation of airway smooth muscle. The effects of Narcan can be solely attributed to the activity of the preservatives present in the vehicles. The mechanism underlying the bronchodilator activity of methyl and propyl hydroxybenzoate is unknown but is not related to receptor blockade or to alterations in the intracellular levels of cyclic AMP.

Animals↗