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PubMedDate not supplied

Haptenic properties of drug metabolites with ortho- or para-aminophenolic structure.

3-Hydroxy-sulfanilamide (3-HS), a biotransformation product of sulfanilamide, 3-hydroxy-para-aminobenzoic acid (3- HPABA ), a biotransformation product of procaine and para-aminobenzoic acid, as well as 5-aminosalicylic acid (5-ASA), a bacterial split product of salicylazosulfapyridine (Sulfasalazine, Salazopyrin ) in the gut, were shown to react spontaneously with and to bind covalently to proteins by simple incubation at alkaline pH. When administered incorporated in incomplete Freund adjuvant into rabbits, the conjugates of these haptens with normal rabbit serum proteins (NRS) give rise to both hapten specific and anti-NRS antibodies. The haptenic properties of these drug metabolites are apparently due to the presence in their molecules of an ortho- or para- aminophenolic structure that renders them capable to generate spontaneously highly reactive quinoneimines . Extensive cross immunological reactions were found between 3-HS, 3- HPABA and ortho-aminophenol (OAP) immunological systems, all of these haptens belonging to the ortho- aminophenolic (ortho- quinoneiminic ) system. Cross reactions were also found between 5-ASA and para-aminophenol (PAP) immunological systems, both of these haptens belonging to the para- aminophenolic (para- quinoneiminic ) system. No cross reactions were, however, found between ortho- and para-aminophenol immunological systems. The so-called "para" group of aminoaromatic compounds is not therefore immunochemically homogeneous. Some compounds included usually in this group give rise in the body to haptens belonging to the ortho- aminophenolic systems, while others belong really to the para- aminophenolic system. Antibodies against NRS proteins which served as carrier in the conjugates were formed by most animals inoculated with such conjugates. (ABSTRACT TRUNCATED AT 250 WORDS)

Aminophenols↗
PubMed1983

Differences in the reactions of isomeric ortho- and para-aminophenols with hemoglobin.

The metabolites of phenacetin, 2-hydroxyphenetidine and 4-nitrosophenetol, rapidly produced ferrihemoglobin both in vivo (dogs) and in vitro. At low concns, 2-hydroxyphenetidine was superior to 4-nitrosophenetol in ferrihemoglobin formation. The kinetics of ferrihemoglobin formation by 2-hydroxyphenetidine in solutions of purified human hemoglobin was biphasic and exhibited an unusual dose response. Similar to p-aminophenols, 2-hydroxyphenetidine was oxidized by oxyhemoglobin, and the oxidation product(s) were reduced by ferrohemoglobin with the formation of ferrihemoglobin. In addition, these oxidation products condensed to 2-amino-7-ethoxy-3H-phenoxazine-3-one (u.v., i.r., 1H-NMR and mass spectroscopy). This metabolite produced ferrihemoglobin by itself and was responsible for the slow phase of ferrihemoglobin formation observed with 2-hydroxyphenetidine. This condensation reaction, which was also observed with 2-aminophenol, prevented thioether formation of the transient o-quinonimines with the cysteine residues of hemoglobin and reduced glutathione as observed with 4-aminophenol and 4-dimethylaminophenol. Phenoxazone formation, which depends on the square of the o-quinonimine concn, was negligible at micromolar concns. At similar concns addition reactions to thiols prevailed also with 2-hydroxyphenetidine and 2-aminophenol. Other electrophilic reactions, e.g. with primary amino groups of amino acids, were insignificant. These dose-dependent differences in the reactions of isomeric aminophenols may explain the low nephrotoxicity of those o-aminophenols capable of forming phenoxazones when given in a single dose. This self-detoxication of some o-quinonimines, however, should not function during long-term exposure to repetitive low doses of such o-aminophenols.

Aminophenols↗
PubMed2003

Construction of Escherichia coli strains for conversion of nitroacetophenones to ortho-aminophenols.

The predominant bacterial pathway for nitrobenzene (NB) degradation uses an NB nitroreductase and hydroxylaminobenzene (HAB) mutase to form the ring-fission substrate ortho-aminophenol. We tested the hypothesis that constructed strains might accumulate the aminophenols from nitroacetophenones and other nitroaromatic compounds. We constructed a recombinant plasmid carrying NB nitroreductase (nbzA) and HAB mutase A (habA) genes, both from Pseudomonas pseudoalcaligenes JS45, and expressed the enzymes in Escherichia coli JS995. IPTG (isopropyl-beta-D-thiogalactopyranoside)-induced cells of strain JS995 rapidly and stoichiometrically converted NB to 2-aminophenol, 2-nitroacetophenone (2NAP) to 2-amino-3-hydroxyacetophenone (2AHAP), and 3-nitroacetophenone (3NAP) to 3-amino-2-hydroxyacetophenone (3AHAP). We constructed another recombinant plasmid containing the nitroreductase gene (nfs1) from Enterobacter cloacae and habA from strain JS45 and expressed the enzymes in E. coli JS996. Strain JS996 converted NB to 2-aminophenol, 2-nitrotoluene to 2-amino-3-methylphenol, 3-nitrotoluene to 2-amino-4-methylphenol, 4-nitrobiphenyl ether to 4-amino-5-phenoxyphenol, and 1-nitronaphthalene to 2-amino-1-naphthol. In larger-scale biotransformations catalyzed by strain JS995, 75% of the 2NAP transformed was converted to 2AHAP, whereas 3AHAP was produced stoichiometrically from 3NAP. The final yields of the aminophenols after extraction and recovery were >64%. The biocatalytic synthesis of ortho-aminophenols from nitroacetophenones suggests that strain JS995 may be useful in the biocatalytic production of a variety of substituted ortho-aminophenols from the corresponding nitroaromatic compounds.

Acetophenones↗
PubMed1988

Degradation of 3-aminophenol by Arthrobacter spec. mA3.

The bacterial strain mA3 capable of utilizing 3-aminophenol as the sole source of carbon, energy and nitrogen for growth was isolated from an enrichment culture and identified as an Arthrobacter species. Utilization of 0.68 mg/ml 3-aminophenol by batch cultures of this organism was characterized by a specific growth rate (mu) of 0.18 h-1 and a yield coefficient (Y) of 0.60. In chemostat cultures of strain mA3 we determined a critical dilution rate (Dc) of 0.175 h-1 by continuous addition of mineral salt medium with 0.5 mg/ml 3-aminophenol. Evidence was obtained that the degradation of catechol by 3-aminophenol induced as well as non-induced cells follows the beta-ketoadipate pathway. The excess ammonium ions, originating from 3-aminophenol degradation and not needed for assimilation were released into the medium. Cells adapted to 3-aminophenol exhibited a high substrate specificity. Among different aromatic substances tested, only catechol and 3,4-dihydroxybenzoate could serve as a carbon source for growth. The importance of the meta position of the amino group for the first step of hydroxylation is discussed in connection with the substrate specificity of whole mA3 cells.

Aminophenols↗
PubMed1994

A spectrophotometric assay for the detection of 2-aminophenols in biological samples.

A sensitive and efficient spectrophotometric assay is described for the determination of 2-aminophenols in biological samples. Using ferric ions as a metal catalyst, 2-aminophenol dimerizes in an acidic aqueous environment to 2-hydroxyisophenoxazin-3-one, an intensively colored dye. The newly developed assay is suitable for the detection of 2-aminophenols in the micromolar range. The paper demonstrates that this chemical assay is also applicable for the determination of 2-aminophenols substituted with a halogen at the ortho, meta, or para position of the aromatic ring with respect to the amino moiety, lambda max, and the molar extinction coefficient varying with the substituent pattern. Results obtained for fluorinated 2-aminophenol detection in biological samples by either this new method or 19F NMR are similar. This observation corroborates that the newly developed assay is suitable for detection of 2-aminophenols in biological samples.

Aminophenols↗
PubMed2004

A novel 2-aminophenol 1,6-dioxygenase involved in the degradation of p-chloronitrobenzene by Comamonas strain CNB-1: purification, properties, genetic cloning and expression in Escherichia coli.

Comamonas strain CNB-1 was isolated from a biological reactor treating wastewater from a p-chloronitrobenzene production factory. Strain CNB-1 used p-chloronitrobenzene as sole source of carbon, nitrogen, and energy. A 2-aminophenol 1,6-dioxygenase was purified from cells of strain CNB-1. The purified 2-aminophenol 1,6-dioxygenase had a native molecular mass of 130 kDa and was composed of alpha- and beta-subunits of 33 and 38 kDa, respectively. This enzyme is different from currently known 2-aminophenol 1,6-dioxygenases in that it: (a) has a higher affinity for 2-amino-5-chlorophenol (K(m)=0.77 microM) than for 2-aminophenol (K(m)=0.89 microM) and (b) utilized protocatechuate as a substrate. These results suggested that 2-amino-5-chlorophenol, an intermediate during p-chloronitrobenzene degradation, is the natural substrate for this enzyme. N-terminal amino acids of the alpha- and beta-subunits were determined to be T-V-V-S-A-F-L-V and M-Q-G-E-I-I-A-E, respectively. A cosmid library was constructed from the total DNA of strain CNB-1 and three clones (BG-1, BG-2, and CG-13) with 2-aminophenol 1,6-dioxygenase activities were obtained. DNA sequencing of clone BG-2 revealed a 15-kb fragment that contained two ORFs, ORF9 and ORF10, with N-terminal amino acid sequences identical to those of the beta- and alpha-subunits, respectively, from the purified 2-aminophenol 1,6-dioxygenase. The enzyme was actively synthesized when the genes coding for the ORF9 and ORF10 were cloned into Escherichia coli.

Amino Acid Sequence↗
PubMed1986

Mechanism of o-aminophenol metabolism in human erythrocytes.

o-Aminophenol was found to be rapidly metabolized to a brown compound in the presence of purified human oxy- and methemoglobin, coupled with the oxidation and reduction of these hemoglobins by o-aminophenol. The final product of o-aminophenol was identified as 2-aminophenoxazine-3-one, by using spectrophotometry and HPLC. The metabolism of o-aminophenol was also observed in human erythrocytes. The production rates of 2-aminophenoxazine-3-one in the cells were very fast, but these were strongly decreased by bubbling carbon monoxide into the cell suspension when intracellular hemoglobin was in the ferrous state. The production of 2-aminophenoxazine-3-one from o-aminophenol in the cells was completely suppressed by cyanide and azide when intracellular hemoglobin was in the ferric state. These results suggest that oxy- and methemoglobin are involved in metabolism of o-aminophenol to 2-aminophenoxazine-3-one in human erythrocytes.

Aminophenols↗
PubMed1984

Thin layer chromatography of p-aminophenol in urine after mixed exposure to aniline and toluene.

A simple method of evaluating p-aminophenol in the urine of people exposed simultaneously to aniline and toluene relies on separating p-aminophenol from hippuric acid and other physiological components of the urine by thin layer chromatography. The adsorbents and developing system have been thus fixed to make possible the separation of p-aminophenol from hippuric acid, urea, and creatinine and their quantitative determination. This method also makes possible the determination of p-aminophenol in urine in the presence of hippuric acid. Hippuric acid is a physiological component of urine and also the metabolite of toluene, so the determination of p-aminophenol is possible also after simultaneous exposure to both compounds: aniline and toluene. At the same time the concentrations of urea and creatinine as additional factors may be determined. The limit of detection of the method is: 5 micrograms/ml for p-aminophenol, 9 micrograms/ml for hippuric acid, 8 micrograms/ml for urea, and 6 micrograms/ml for creatinine.

Aminophenols↗
PubMed1990

Hydroxyurea and p-aminophenol are the suicide inhibitors of ascorbate peroxidase.

Guaiacol peroxidase from spinach catalyzes the oxidation of p-aminophenol to produce the aminophenoxy radical as the primary product which is converted further into a stable oxidation product with an absorption peak at 470 nm. The p-aminophenol radicals oxidize ascorbate (AsA) to produce monodehydroascorbate radicals. Kinetic analysis indicates that p-aminophenol radicals also oxidize monodehydroascorbate to dehydroascorbate. Incubation of AsA peroxidase from tea leaves and hydrogen peroxide with p-aminophenol, p-cresol, hydroxyurea, or hydroxylamine results in the inactivation of the enzyme. No inactivation of the enzyme was found upon incubation of the enzyme with these compounds either in the absence of hydrogen peroxide or with the stable oxidized products of these compounds. The enzyme was protected from inactivation by the inclusion of AsA in the incubation mixture. The radicals of p-aminophenol and hydroxyurea were produced by AsA peroxidase as detected by their ESR signals. These signals disappeared upon the addition of AsA, and the signal characteristic of monodehydroascorbate was found. Thus, AsA peroxidase is inactivated by the radicals of p-aminophenol, p-cresol, hydroxyurea, and hydroxylamine which are produced by the peroxidase reaction, and it is protected from inactivation by AsA via the scavenging of the radicals. Thus, these compounds are the suicide inhibitors for AsA peroxidase. Isozyme II of AsA peroxidase, which is localized in chloroplasts, is more sensitive to these compounds than isozyme I. In contrast to AsA peroxidase, guaiacol peroxidase was not affected by these various compounds, even though each was oxidized by it and the corresponding radicals were produced.

Aminophenols↗
PubMed1977

Possible multiple binding sites for o-aminophenol on uridine diphosphate glucuronyltransferase.

1. Hepatic microsomal UDP-glucuronyltransferase (EC 2.4.1.17) derived from either weanling or adult rats exhibits three pH optima, at pH 5.4, 7.2 and 9.2, when o-aminophenol is the acceptor substrate, whereas p-nitrophenol is the acceptor substrate only on pH optimum is observed, at pH 5.4.2. Prior treatment of rats of either age with 3-methylcholanthrene results in a 2-3-fold increase in o-aminophenol conjugation at pH 5.4 and a 6-9-fold increase at pH 9.2. At pH 7.2, the induced enzyme is 2 to 3 times more active towards o-aminophenol than the control enzyme, but no pH optimum is demonstrable. 3. o-Aminophenol conjugation at pH 5.4 and 9.2 is inhibited competitively by both p-nitrophenol and p-nitrophenyl glucuronide, suggesting that the two phenolic aglycones share the same binding site. At pH 7.2, however, p-nitrophenyl glucuronide does not inhibit o-aminophenol conjugation, suggesting that the binding site at this pH is not shared by the two phenols. These data are consistent with the existence of more than one binding site for o-aminophenol on UDP-glucuronyltransferase.

Aniline Compounds↗
PubMed1983

Inhibition of prostaglandin synthetases derived from neuronal and glial cells and rat renal medulla by ortho-, meta- and para-substituted aminophenolic compounds.

Acetophenetidines, acetamidophenols, phenetidines and aminophenols substituted in o-, m- or p-position inhibit prostaglandin-synthetases originating from C 1300 mouse neuroblastoma cells (clone N2A), rat astrocytoma cells (clone C 6) and rat renal medulla. Desacetylated compounds were more potent inhibitors than their corresponding acetyl derivatives and many o- and m-analogues were more active than p-substituted structures like paracetamol (p-acetamidophenol) or phenacetin (p-acetophenetidine). When twelve o-, m- or p-aminophenolic test compounds were compared to acetylsalicyclic acid and indomethacin, o-, and p-phenetidine and o-aminophenol were as effective as acetylsalicyclic acid. All aminophenol derivatives which inhibited prostaglandin synthesis suppressed cultured nervous cell and kidney cyclo-oxygenases to similar extents. Our results suggest that aminophenolic drugs are not more effective against prostaglandin-synthetases in the CNS than against those in the periphery.

Acetaminophen↗
PubMed1996

Nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol in Fischer 344 rats: comparisons with 2- and 4-chloroaniline and 2- and 4-aminophenol.

Nephrotoxicity occurs following intraperitoneal (i.p.) administration of 2-chloroaniline or 4-chloroaniline hydrochloride to Fischer 344 rats, but the nephrotoxicant chemical species and mechanism of nephrotoxicity are unknown. The purpose of this study was to evaluate the in vivo and in vitro nephrotoxic potential of 2-amino-5-chlorophenol and 4-amino-3-chlorophenol, metabolites of 4-chloroaniline and 2-chloroaniline. A comparison was also made between the nephrotoxic potential of the aminochlorophenols and the corresponding aminophenols to examine the effect of adding a chloride group on the nephrotoxic potential of the animophenols. Male Fischer 344 rats (4/group) were given an i.p. injection of a chloroaniline or aminochlorophenol hydrochloride (1.5 mmol/kg), and aminophenol (1.0 or 1.5 mmol/kg), or vehicle, and renal function monitored at 24 and 48 h. Both aminochlorophenols induced smaller and fewer renal effects that the parent chloroanilenes in vivo. Also, 4-aminophenol was markedly more potent as a nephrotoxicant that 4-amino-3-chlorophenol, while 2-aminophenol and 2-amino-5-chlorophenol induced only mild change in renal function. In vitro, the phenolic compounds reduce p-aminohippurate accumulation by renal cortical slices at bath concentrations of 0.01 mM, while a bath concentration of 0.50 mM or greater was required for the chloroanilines. However, all compounds reduced tetraethylammonium accumulation at bath concentrations of 0.1-0.5 mM or greater. These results indicate that extrarenally-produced aminochlorophenol metabolites do not contribute to the mechanism of chloroaniline nephrotoxicity. Also, the reduced nephrotoxic potential of 4-amino-3-chlorophenol compared to 4-aminophenol could result from an altered ability of the aminochlorophenol to redox cycle or form conjugates.

Aminophenols↗
PubMed1965

SOME DIFFERENCES IN THE CONJUGATION OF O-AMINOPHENOL AND P-NITROPHENOL BY THE URIDINE DIPHOSPHATE TRANSGLUCURONYLASE OF MOUSE-LIVER HOMOGENATES.

1. Glucuronide synthesis from uridine diphosphate glucuronate and o-aminophenol or p-nitrophenol in the presence of uridine diphosphate transglucuronylase of mouse-liver homogenates has been studied with respect to inhibition by compounds known to be conjugated under the experimental conditions, and also by thiophenol. 2. Raising the o-aminophenol concentration decreased the inhibition of o-aminophenyl glucuronide synthesis by the alternative glucuronyl acceptors phenol, menthol and benzoic acid, but was without effect on that caused by p-nitrophenol and thiophenol. 3. Raising the p-nitrophenol concentration decreased or abolished the inhibition of p-nitrophenyl glucuronide synthesis due to phenol, menthol, benzoic acid, anthranilic acid, o-aminophenol and thiophenol. 4. The o-aminophenol system was much more readily inhibited by all compounds than the p-nitrophenol system. 5. In tris buffer, pH7.4, over 30% activation of the o-aminophenol system was achieved by 2mm-Mg(2+), but 10mm-Mg(2+) was inhibitory. The p-nitrophenol system showed only inhibition from 2mm-Mg(2+) upwards. 6. The results are discussed as suggesting that there are at least two uridine diphosphate transglucuronylases.

Aminophenols↗
PubMed2000

Oscillatory oxido-reductive reaction of intracellular hemoglobin in human erythrocyte incubated with o-aminophenol.

When human erythrocytes were incubated with o-aminophenol at pH 7.0 at 37 degrees C for 46 hours, intracellular oxyhemoglobin was completely oxidized to methemoglobin during the initial 6 hours, and methemoglobin formed was then reduced to oxyhemoglobin during the following 20 hours. This was demonstrated by the changes in absorption spectra of intracellular hemoglobin. Such oscillatory behavior of intracellular hemoglobin during reaction with o-aminophenol was explained by the fact that o-aminophenol has the ability to both oxidize oxyhemoglobin and reduce methemoglobin. In order to study the mechanism of oxido-reductive reactions of hemoglobin with aromatic reductants including o-aminophenol, the oxidation of ferrous hemoglobin and reduction of methemoglobin with various aromatic reductants such as o-aminophenol, 2-amino-4-methyl-phenol, 2-amino-5-methylphenol, and homogentisic acid were investigated under various conditions. It was found that oxyhemoglobin was oxidized by these aromatic compounds, and the oxidation rate was accelerated in the presence of inositol hexaphosphate, but was not affected in the presence of catalase and superoxide dismutase, except for the case with homogentisic acid. The oxidation of ferrous hemoglobin by these compounds did not proceed under anaerobic conditions. Methemoglobin was reduced by these aromatic compounds, and the reduction rate was much accelerated in the presence of inositol hexaphosphate, but was not affected in the presence of catalase and superoxide dismutase, except for the case with homogentisic acid. The reduction of methemoglobin by these compounds proceeded under anaerobic conditions, suggesting that ferric heme of hemoglobin reacts directly with aromatic reductants. On the basis of these results, the mechanism of oxido-reductive reaction of ferrous and ferric hemoglobin with aromatic reductants was proposed.

Aminophenols↗
PubMed1991

Para-aminophenol and structurally related compounds as intermediates in lipofuscin formation and in renal and other tissue toxicities.

P-aminophenol is considered a minor nephrotoxic metabolite of phenacetin and acetaminophen (paracetamol) in man. Our experiments show that p-aminophenol readily undergoes oxidative polymerization during incubation in human blood or plasma, to form melanin, as a component of soluble lipofuscin. Haemolysis accompanies this process in whole blood. Unmetabolized phenacetin and acetaminophen do not form soluble lipofuscins. Long-term excessive use of phenacetin or acetaminophen has been associated with chronic renal disease, haemolytic anaemia, and increased solid lipofuscin deposition in tissues. Excessive use of phenacetin has also been associated with cancer of renal pelvis and bladder. It appears to us that p-aminophenol and other o- and p-aminophenol metabolites of these drugs are intermediates not only in the etiology of chronic renal disease, but in the other developments as well. P-aminophenol and other ex(end)ogenous aminohydroxyphenyl, aminopolyhydroxyphenyl, polyhydroxyphenyl and polyaminophenyl compounds with these groups in ortho and para positions (such as 3-hydroxyanthranilic acid, 6-aminodopamine, dopamine, p-phenylenediamine, etc.) can undergo autoxidations and metal-catalyzed and enzymatic oxidations in man to produce toxic (semi)quinones(imines), (semi)quinonediimines and reactive oxygen species. After depletion of antioxidants these very reactive (semi)quinones(imines) and (semi)quinonediimine intermediates, many of which are precursors of plasma soluble lipofuscins and melanoproteins, react with essential proteins, DNA, other macromolecules and can cause or contribute to renal and other tissue toxicity, haemolytic anaemia, neoplasia, and granular lipofuscin formation. The reactive oxygen species can also deplete antioxidants, damage essential proteins, DNA, and other macromolecules, and thereby injure cells and extracellular matrix.

Adult↗
PubMed1979

p-Aminophenol fluorescence and determination in the presence of acetaminophen.

The spectrophotometric and fluorometric properties of the aminophenols and of several compounds related to p-aminophenol were examined. A direct spectrofluorometric method for p-aminophenol determination at trace levels in methanol was developed and evaluated for the effect of inner filtering by acetaminophen. The method was applied to the determination of p-aminophenol as an impurity in acetaminophen and acetaminophen-containing tablets.

Acetaminophen↗
PubMed1995

The effect of varying halogen substituent patterns on the cytochrome P450 catalysed dehalogenation of 4-halogenated anilines to 4-aminophenol metabolites.

The cytochrome P450 catalysed biotransformation of 4-halogenated anilines was studied in vitro with special emphasis on the dehalogenation to 4-aminophenol metabolites. The results demonstrated that a fluorine substituent at the C4 position was more easily eliminated from the aromatic ring than a chloro-, bromo- or iodo-substituent. HPLC analysis of in vitro biotransformation patterns revealed that the dehalogenation of the C4-position was accompanied by formation of non-halogenated 4-aminophenol, without formation of NIH-shifted metabolites. Changes in the apparent Vmax for the microsomal oxidative dehalogenation appeared to correlate with the electronegativity of the halogen substituent at C4, the fluorine substituent being the one most easily eliminated. A similar decrease in the rate of dehalogenation from a fluoro- to a chloro- to a bromo- to an iodo-substituent was observed in a system with purified reconstituted cytochrome P450 IIB1, in a tertiair butyl hydroperoxide supported microsomal cytochrome P450 system as well as in a system with microperoxidase 8. This microperoxidase 8 is a haem-based mini-enzyme without a substrate binding site, capable of catalysing cytochrome P450-like reaction chemistry. Together, these results excluded the possibility that the difference in the rate of dehalogenation with a varying C4-halogen substituent arose from a change in the contribution of cytochrome P450 enzymes involved in oxidative dehalogenation with a change in the halogen substituent. Rather, they strongly suggested that the difference was indeed due to an intrinsic electronic parameter of the various C4 halogenated anilines dependent on the type of halogen substituent. Additional in vitro experiments with polyfluorinated anilines demonstrated that elimination of the C4-fluorine substituent became more difficult upon the introduction of additional electron withdrawing fluorine substituents in the aniline-ring. 19F-NMR analysis of the metabolite patterns showed that the observed decrease in 4-aminophenol formation was accompanied by a metabolic switch to 2-aminophenols and N-hydroxyanilines, while products resulting from NIH-type mechanisms were not observed. For a C4-chloro-, bromo-, or iodo-substituted 2-fluoroaniline the Vmax for the oxidative dehalogenation was reduced by the additional electron withdrawing fluorine substituent at the C2 position in a similar way.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminophenols↗
PubMed1979

The nephrotoxicity of p-aminophenol. II. The effect of metabolic inhibitors and inducers.

Inducers and inhibitors of the microsomal mixed function oxidase system have no consistent effect upon the nephrotoxicity of p-aminophenol, or on binding of the compound in vivo to cell protein. p-[ring-3H]Aminophenol was bound in vitro to kidney microsomal protein and to a lesser extent to liver. The binding was enhanced by preincubation of the p-aminophenol in air and inhibited by ascorbate, GSH, N2 and NADPH. These findings indicate that in contrast to paracetamol hepatoxicity which is dependent upon the mixed function oxidase system, that nephrotoxicity of p-aminophenol is dependent upon oxidation to a toxic metabolite by some other pathway. A similar metabolite may be responsible for the nephrotoxic action of phenacetin.

Aminophenols↗