Disease relevance of Phenetidine

• Phenacetin, p-phenetidine, and PNOH all produced dose-dependent methemoglobinemia in rats [1].
• These data suggest that the toxicity of p-phenetidine is similar to that of its structural analog aniline [2].

High impact information on Phenetidine

• Prostaglandin synthase and horseradish peroxidase catalyzed DNA-binding of p-phenetidine [3].
• Arylamine N-acetyltransferase activity (A-NAT: E.C.2.3.1.5) from Rana perezi retina was studied using p-phenetidine as specific substrate [4].
• Subcellular localization in neural retina indicated that both enzymatic activities are in the supernatant fraction (39,000 g, 20 min). p-Phenetidine acetylation was linear as a function of the neural retina amount in the assay (1/16 to 1 retina), and it is insensitive to phosphate buffer pH in the range 6.5-8 [4].
• Kinetic constants were KM = 11.2 microM, Vmax = 0.49 nmol/h/mg prot. for p-phenetidine (50 microM acetyl-CoA), and KM = 113.4 microM, Vmax = 3.1 nmol/h/mg prot. for acetyl-CoA (5 mM p-phenetidine) [4].
• It is suggested that there are two forms of retinal A-NAT, and that, under specified conditions, the activity of one form (A-NAT; p-phenetidine) may be regulated in an opposite manner to AA-NAT activity [5].

Chemical compound and disease context of Phenetidine

• Both DTC and CS2 also suppressed p-phenetidine-induced methemoglobinemia with a delay in plasma p-phenetidine disappearance [6].
• The suppression of methemoglobinemia by DTC and CS2 may result from an inhibition of metabolic conversion of p-phenetidine to methemoglobin-forming substances such as N-hydroxy-p-phenetidine which is of most importance, p-aminophenol and 2-hydroxy-p-phenetidine by the microsomal cytochrome P-450-containing monooxygenase system in the liver [6].

Biological context of Phenetidine

• Unlike the AA-dependent reaction, the H2O2-supported reaction showed no inhibition of protein binding at higher p-phenetidine concns [7].
• The substrate specificity of these enzymes were examined with p-phenetidine, 2-aminofluorene, tryptamine and phenylethylamine as substrates [8].
• This article addresses results from a single 4-h and repeated 1- and 4-wk inhalation exposure studies in Wistar rats with vapor and/or aerosol atmospheres of 4-ethoxyaniline (p-phenetidine) [2].
• The effects of addition of purified NADPH-cytochrome c (P-450) reductase on microsomal activities of aniline hydroxylation, p-phenetidine O-deethylation and ethylmorphine and aminopyrine N-demethylations were investigated utilizing microsomes from untreated, phenobarbital-treated and 3-methylcholanthrene-treated rats [9].

Anatomical context of Phenetidine

• The data in this report are consistent with a peroxidatic activation of p-phenetidine possibly involving an amine radical catalyzed by prostaglandin synthase (PGS) present in RSV microsomes as well as by other peroxidases [7].
• p-Phenetidine is metabolized by ram seminal vesicle (RSV) microsomes, horseradish peroxidase (HRP) and rat liver microsomes to protein-binding products [7].
• The binding ratio of 14C-ring to 14C-ethyl labeled p-phenetidine using rabbit kidney medulla microsomal protein was 2:1 suggesting that the binding species may be p-phenetidine quinone-imine and quinone-diimine dimers which have been shown previously to be products of the peroxidatic oxidation of p-phenetidine [10].
• The interaction of N-(4-ethoxyphenyl)p-benzoquinone imine (NEPBQI), a metabolite formed during peroxidase catalyzed metabolism of p-phenetidine, with GSH and its effects in isolated rat hepatocytes were investigated [11].
• Somewhat higher, micromolar, concentrations of p-phenetidine also reduced COX-2 expression in neutrophils [12].

Associations of Phenetidine with other chemical compounds

• The metabolism of p-phenetidine in microsomes from rabbit kidney and the metabolism of acetaminophen and p-phenetidine in human kidney microsomes to protein binding metabolites were examined [10].
• That p-phenetidine radicals were produced during horseradish peroxidase catalyzed oxidation of p-phenetidine was supported by experiments using the spin probe OXANOH [13].
• NADH-synergism of NADPH-dependent o-dealkylation of type II compounds, p-anisidine and p-phenetidine, in rat liver microsomes [14].
• We suggest that the very potent inhibitory activity of p-phenetidine on PGE2 synthesis combined with the reduction of COX-2 expression could explain the renal papillary necrosis in phenacetin kidney [12].
• The ESR spectrum of the conjugate base of the 4-ethoxyaniline cation radical, the neutral 4-ethoxyphenazyl free radical, was obtained at pH 11-12 by the oxidation of p-phenetidine with potassium permanganate [15].

Gene context of Phenetidine

• Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro [12].
• In vitro, methemoglobin formation by p-phenetidine was decreased in liver microsomes isolated from DTC- or CS2-treated mice [6].
• Guinea pigs were sensitized by p-phenetidine (PT), 2-hydroxy-p-phenetidine (HPT) as well as by conjugates prepared by reacting PT and HPT with proteins in vitro [16].

References