[Comparative toxicological characteristics of para- and ortho-aminophenols, para-chloro-ortho-aminophenol and para-nitro-ortho-aminophenol].
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Animals↗
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Comparative cytotoxic effects of acetaminophen (N-acetyl-p-aminophenol), a non-hepatotoxic regioisomer acetyl-m-aminophenol and their postulated reactive hydroquinone and quinone metabolites in monolayer cultures of mouse hepatocytes.
Toxic effects of acetaminophen (paracetamol, N-acetyl-p-aminophenol, APAP) in monolayer cultures of mouse hepatocytes developed over a period of 18 hr. N-Acetyl-m-aminophenol (AMAP) was approximately 10-fold less toxic than APAP, despite the fact that it bound covalently to a greater extent to hepatocyte macromolecules. AMAP did not deplete glutathione to as great an extent as APAP, indicating that their reactive metabolites may bind to different proteins or that oxidative damage in addition to arylation of proteins may be involved in the development of cell death. The toxicity of 3-methoxy-acetyl-p-aminophenol was similar to that of APAP, whereas the other hydroquinone and quinone metabolites were 8-10 times more cytotoxic than APAP. The potencies of these analogs were in the order: acetyl-m-aminophenol-p-benzoquinoneimine greater than or equal to 2,5-dihydroxyacetanilide greater than or equal to 3-methoxy-p-benzoquinone greater than or equal to N-acetyl-p-benzoquinone imine (NAPQI) greater than or equal to acetyl-m-aminophenol-o-benzoquinone greater than or equal to 3-hydroxy-acetyl-p-aminophenol. The relative toxic potencies of the hydroquinone and quinone metabolites of AMAP were comparable to that of NAPQI, and do not readily explain the marked difference between the cytotoxic effects of AMAP and APAP.
Acetaminophen↗
The role of p-aminophenol in acetaminophen-induced nephrotoxicity: effect of bis(p-nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity and metabolism in Fischer 344 rats.
Acetaminophen (APAP) produces proximal tubular necrosis in Fischer 344 (F344) rats. Recently, p-aminophenol (PAP), a known potent nephrotoxicant, was identified as a metabolite of APAP in F344 rats. The purpose of this study was to determine if PAP formation is a requisite step in APAP-induced nephrotoxicity. Therefore, the effect of bis(p-nitrophenyl) phosphate (BNPP), an acylamidase inhibitor, on APAP and PAP nephrotoxicity and metabolism was determined. BNPP (1 to 8 mM) reduced APAP deacetylation and covalent binding in F344 renal cortical homogenates in a concentration-dependent manner. Pretreatment of animals with BNPP prior to APAP or PAP administration resulted in marked reduction of APAP (900 mg/kg) nephrotoxicity but not PAP nephrotoxicity. This result was not due to altered disposition of either APAP or acetylated metabolites in plasma or renal cortical and hepatic tissue. Rather, BNPP pretreatment reduced the fraction of APAP excreted as PAP by 64 and 75% after APAP doses of 750 and 900 mg/kg. BNPP did not alter the excretion of APAP or any of its non-deacetylated metabolites nor did BNPP alter excretion of PAP or its metabolites after PAP doses of 150 and 300 mg/kg. Therefore, the BNPP-induced reduction in APAP-induced nephrotoxicity appears to be due to inhibition of APAP deacetylation. It is concluded that PAP formation, in vivo, accounts, at least in part, for APAP-induced renal tubular necrosis.
Acetaminophen↗
Synthesis and evaluation of esters of N,N-bis(2-chloroethyl)-p-aminophenol and N,N-bis(2-bromoethyl)-p-aminophenol as potential antitumor agents.
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Animals↗
p-aminophenol nephrotoxicity: biosynthesis of toxic glutathione conjugates.
p-Aminophenol causes necrosis of the pars recta of the proximal tubules in rats, and its nephrotoxicity may be due to glutathione-dependent bioactivation reactions. We have investigated the hepatic metabolism of p-aminophenol in Wistar rats and the cytotoxicity of formed glutathione S-conjugates in rat renal epithelial cells. After ip application of p-aminophenol (100 mg/kg), the following metabolites were identified in rat bile: 4-amino-2-(glutathion-S-yl)phenol, 4-amino-3-(glutathion-S-yl)-phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol, an aminophenol conjugate (likely a sulfate or glucuronide), acetaminophen glucuronide, and 3-(glutathion-S-yl)acetaminophen. 4-Amino-3-(glutathion-S-yl)phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, and 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol induced a dose- and time-dependent loss of cell viability in rat kidney cortical cells. Cell killing was significantly reduced by inhibition of gamma-glutamyl transpeptidase with Acivicin. p-Aminophenol was also toxic to renal epithelial cells. Coincubation of p-aminophenol with tetraethylammonium bromide, a competitive inhibitor of the organic cation transporter, and with SKF-525A, an inhibitor of cytochrome P450, protected cells from p-aminophenol-induced toxicity. p-Aminophenol would thus be accumulated in the kidney mainly by organic cation transport systems, which are concentrated in the S-1 segment of the proximal tubule. However, p-aminophenol toxicity in vivo is directed toward the S-2 and S-3 segments, which are rich in gamma-glutamyl transpeptidase. These results and the observation that biliary cannulation and glutathione depletion reduce p-aminophenol nephrotoxicity suggest that the biosynthesis of toxic glutathione conjugates is responsible for p-aminophenol nephrotoxicity in vivo. The aminophenol glutathione S-conjugates formed induce p-aminophenol nephrotoxicity by a pathway dependent on gamma-glutamyl transpeptidase.
Aminophenols↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
p-Aminophenol induced DNA damage and cytotoxicity enhanced by autoxidation.
p-Aminophenol inhibits DNA synthesis and alters the structure of DNA. A decrease in sedimentation of nucleoids from cells treated with p-aminophenol was observed and this decrease in sedimentation was considerably less when cells were incubated with p-aminophenol in an atmosphere of nitrogen or at lower pH values. This compound was also shown to be cytotoxic to cells in culture. These results demonstrate that conditions retarding the autoxidation of p-aminophenol lead to reduced effects on DNA structure and a lesser cytotoxic effect.
Aminophenols↗
The metabolism of aminophenols in erythrocytes.
1. Like 2- and 4-dimethylaminophenol, 4-aminophenol in the presence of oxyhaemoglobin forms numerous adducts with glutathione (GSH). Using 14C-4-aminophenol and 3H-glutathione, ten different thioethers were isolated, by h.p.l.c., with isotope ratios of 1:1, 1:2, 1:3, respectively. The structural identification of the different thioethers is under current investigation. 2. In erythrocytes of human and dog, and in dog blood, in vivo, the same pattern of 4-aminophenol conjugates with GSH was found. 3. In vivo, 5% of administered 4-aminophenol is converted into thioethers within erythrocytes, accompanied by a 60% decrease in the cellular GSH, indicating the role of erythrocytes in the biotransformation of xenobiotics.
Aminophenols↗
Studies of paracetamol/phenacetin toxicity: isolation and characterization of p-aminophenol-glutathione conjugate.
1. p-Aminophenol, a minor metabolite of phenacetin, is a potent nephrotoxic agent. 2. We have examined the binding of p-aminophenol to glutathione (GSH), a model amino acid, in the presence of horseradish peroxidase, which catalyses one electron oxidation. 3. The reaction product was purified by preparative h.p.l.c., and its structure was determined by FAB mass spectrometry and 1H-n.m.r. to be a p-aminophenol-GSH conjugate. The conjugate was formed between the ortho carbon of the amino group of p-aminophenol and the SH group of GSH. 4. It was confirmed by h.p.l.c. and 1H-n.m.r. that formation of the conjugate was catalysed in vitro by rat liver microsomes and cumene hydroperoxide.
Acetaminophen↗
Mechanisms of cancerogenesis inhibition. II. The aminophenols and their oxidation products.
The protective effect exerted by a series of aminophenols (12 compounds) against in vitro DNA interaction with (3H)benzo(a)pyrene activated by methylcholanthrene-stimulated microsomes was determined. In agreement with theoretical calculations the inhibitory effectiveness of aminophenols was of the same order of magnitude (between 15-50% protection) as for the phenolic antioxidants. According to our previous findings, this protection is due to the inhibition of cytochrome P-450-dependent microsomal monooxygenases. However, most unexpectedly, it was also found that oxidation products of 4-aminophenol and 4-N-methylaminophenol are significantly more effective than their reduced precursors (protection greater than 95%). The structure of the inhibitory oxidation products of the aminophenols is unknown. However, indirect arguments suggest that some quinoneimines formed as reactive intermediates during the oxidation process could be responsible for this effect. A similar phenomenon was previously found for this effect. A similar phenomenon was previously found for the quinones--diphenols corresponding pairs.
Aminophenols↗
Catalytic oxidation of 2-aminophenols and ortho hydroxylation of aromatic amines by tyrosinase.
The usual substrates of tyrosinase, a copper-containing monooxygenase (EC 1.14.18.1), are monophenols and o-diphenols which are both converted to o-quinones. In this paper, we studied the reaction of this enzyme with two new classes of substrates: aromatic amines and o-aminophenols, structural analogues of monophenols and o-diphenols, respectively. They undergo the same catalytic reactions (ortho hydroxylation and oxidation), as documented by product analysis and kinetic studies. In the presence of tyrosinase, arylamines and o-aminophenols are converted to o-quinone imines, which are isolated as quinone anils or phenoxazones. As an example, in the presence of tyrosinase, 2-amino-3-hydroxybenzoic acid (an o-aminophenol) is converted to cinnabarinic acid, a well-known phenoxazone, while p-aminotoluene (an aromatic amine) gives rise to the formation of 5-amino-2-methyl-1,4-benzoquinone 1-(4-methylanil). Kinetic studies using an oxygen electrode show that arylamines and the corresponding monophenols exhibit similar Michaelis constants (Km = 0.11-0.49 mM). In contrast, the reaction rates observed for aromatic amines are relatively slow (Kcat = 1-3 min-1) as compared to monophenols (1320-6960 min-1). The enzymatic conversion of arylamines by tyrosinase is different from the typical ones: N-oxidation and ring hydroxylation without further oxidation. This difference originates from the regiospecific hydroxylation (ortho position) and subsequent oxidation of the intermediate o-aminophenol to the corresponding o-quinone imine. Finally, the well-known monooxygenase activity of tyrosinase was also confirmed for the aromatic amine p-aminotoluene, with 18O2.(ABSTRACT TRUNCATED AT 250 WORDS)
Amines↗
Pigment production by Cryptococcus neoformans and other Cryptococcus species from aminophenols and diaminobenzenes.
Cryptococcus neoformans and other Cryptococcus species can produce pigment(s) from many aminophenol and diaminobenzene compounds. Pigment production from these compounds is similar to the conversion of diphenols to melanin by C. neoformans. Several pigmentation patterns (resulting in the identification or grouping of Cryptococcus species) have been observed by using diaminobenzene and aminophenol compounds as substrates. The most common pigmentation pattern observed was pigment production by both C. neoformans and C. terreus. In contrast to the diphenols, only two aminophenols (4-hydroxymetanilamide and 3-aminotyrosine) were found to be highly specific as substrates. They allowed only C. neoformans to produce pigment. When 4-aminosalicylic acid was the substrate, a unique pattern was observed because only C. terreus, C. diffluens, and C. albidus produced pigment. Finally, a pattern was observed in which C. neoformans produced large amounts of pigment from aminophenol and diaminobenzene compounds, whereas the other Cryptococcus species produced smaller amounts. A simplified scheme with three substrates resulted in the identification of C. terreus and C. neoformans as well as two groups of other Cryptococcus species, group I (C. albidus and C. diffluens) and group II (C. laurentii and C. luteolus).
Aminobenzoates↗