Gerhard Renner

Urinary excretion of N-hydroxy derivatives of some aromatic amines by rabbits, guinea pigs, and dogs☆

Abstract The N-hydroxy derivatives of p-ethylaniline, p-chloroaniline, p- and maminopropiophenone, 4-aminobiphenyl, and 2-aminofluorene were found in the urine after injection. Rabbits excrete 30 per cent of the p-aminopropiophenone and 20 per cent of the 4-aminobiphenyl as N-hydroxy derivative. The N-hydroxy derivatives of the other amines appear in the urine to a much smaller extent. Guinea pigs excrete a smaller proportion of the amines as N-hydroxy derivative than rabbits; 15 per cent of p-amino-propiophenone was found in the urine as N-hydroxy derivative. Dogs excrete only 1 per cent or less of the amines tested as N-hydroxy derivative. N-Hydroxy-p-amino-propiophenone is excreted to a large extent as a conjugate which is split in acid solution. The fraction of p-aminopropiophenone excreted as N-hydroxy derivative is the same over a wide range of doses. The relationship between the concentration of N-hydroxy derivative, and nitroso analogue, in the blood and urine of rabbits is quite different from that observed in dogs.

Hexachlorobenzene and its metabolism

This overview of the metabolism of the fungicide hexachlorobenzene (HCB) reviews the extensive metabolic studies and the numerous metabolites found in animals. The complex processes of the metabolic pathways of HCB into sulfur‐containing metabolites, or into non‐sulfur‐containing phenolic metabolites, or into non‐sulfur‐ and non‐oxygen‐containing metabolites, are discussed and presented. The toxicities of several metabolites of HCB are reported.

Acute toxicities of pentachlorophenol, pentachloroanisole, tetrachlorohydroquinone, tetrachlorocatechol, tetrachlororesorcinol, tetrachlorodimethoxybenzenes and tetrachlorobenzenediol diacetates administered to mice

Pentachlorophenol (PCP), pentachloroanisole (PCAS), tetrachlorohydroquinone (TCH), tetrachlorocatechol (TCC), tetrachlororesorcinol (TCR), tetrachlorohydroquinone dimethyl ether (TCH‐DME), tetrachlorocatechol dimethyl ether (TCC‐DME), tetrachlororesorcinol dimethyl ether (TCR‐DME), tetrachlorohydroquinone diacetate (TCH‐DA), tetrachlorocatechol diacetate (TCC‐DA), and tetrachlororesorcinol diacetate (TCR‐DA), were investigated for their acute toxicity in male (m) and female (f) mice. The substances were administered orally and intraperitoneally, respectively. The oral LD50 values were: 129±9 (m) and 134±9 (f) mg/kg for PCP, 318±22 (m) and 331±22 (f) mg/kg for PCAS, 318±22 (m) and 331±22 (f) mg/kg for TCC, 368±26 (m) and 383±26 (f) mg/kg for TCH, and 736±52 (m) and 767±51 (f) for TCR. The intraperitoneal LD50 values were: 59±4 (m) and 61±4 (f) mg/kg for PCP, 281 ±20 (m) and 293±20 (f) mg/kg for PCAS, 161±11 (m) and 167±11 (f) mg/kg for TCC, 28±2 (m) and 30±2 (f) mg/kg for TCH, and 351±25 (m) and 366±24 (f)...

Mechanism of the autocatalytic formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide

SummaryIncubation with ferrihemoglobin or ferricytochrome c transforms N,N-dimethylaniline-N-oxide into N-methylaniline, formaldehyde, N,N-dimethylaniline, 2-dimethylaminophenol, 4-dimethylaminophenol, and a violet dye. The amines and aminophenols were isolated and identified; the structure of the dye is not yet known. Deoxygenated ferrohemoglobin was found to decompose N,N-dimethylaniline-N-oxide much more slowly than ferrihemoglobin. This explains the autocatalytic course of the formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide. The ferrihemoglobin forming derivatives of N,N-dimethylaniline-N-oxide, i.e. 4-dimethylaminophenol, 2-dimethylaminophenol, and the dye, are produced more rapidly when the ferrihemoglobin concentration increases. Ferricytochrome c accelerates the formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide, because it produces the ferrihemoglobin forming derivatives more rapidly than ferrihemoglobin itself. Oxygen is needed for the formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide, since it is not the N-oxide itself that oxidizes hemoglobin, but the dimethylaminophenols and the dye which transfer electrons from ferrohemoglobin to molecular oxygen. The kinetics of these reactions was studied.

Urinary metabolites of N,N-dimethylaniline produced by dogs

SummaryFrom urine of dogs injected with N,N-dimethylaniline the following metabolites were isolated as crystalline hydrochlorides and identified by their UV and IR spectra: 4-aminophenol, 4-methylaminophenol, 4-dimethylaminophenol, 2-aminophenol, and N-methylaniline. 2-Dimethylaminophenol was identified only by UV spectra, as the amount of crystalline hydrochloride was too small for an IR spectrum. The presence of 2-methylaminophenol in the urine was demonstrated by Rf values of the compound and its oxalate and color reaction. Aniline was not found in urine of the dogs injected with N,N-dimethylaniline, but nearly 2×10−5 M aniline was determined in the blood of dogs injected with N,N-dimethylaniline, 40 mg/kg.

N-Hydroxylation of 2-aminofluorene in the guinea pig and by guinea pig liver microsomes in vitro.

SummaryN-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 ISOLATION OF P-CHLORONITROSOBENZENE FROM THE BLOOD OF DOGS INJECTED WITH P-CHLOROANILINE.

SummaryThe products resulting from the biological N-oxidation of p-chloroaniline (p-chlorophenylhydroxylamine and p-chloronitrosobenzene) were extracted as p-chloronitrosobenzene into hexane from the blood of dogs injected with p-chloroaniline. After purification by countercurrent distribution and adsorption on silica gel, steam distillation yielded a solid substance. Its melting point and other physical and chemical properties were found to be identical with those of authentic p-chloronitrosobenzene.ZusammenfassungDie Produkte der biologischen N-Oxydation des p-Chloranilins (p-Chlorphenylhydroxylamin und p-Chlornitrosobenzol) wurden aus dem Blute von Hunden, denen p-Chloranilin injiziert worden war, als p-Chlornitrosobenzol mit Hexan extrahiert. Nach Reinigung durch Gegenstromverteilung und Chromatographie an Silicagel wurde durch Wasserdampfdsetillation eine feste Substanz erhalten, die sich im Schmelzpunkt und anderen physikalischen und chemischen Eigenschaften mit authentischen p-Chlornitrosobenzol identisch erwies.

The hydrolysis of acetanilide and some of its derivatives by enzymes in the microsomal and soluble fraction prepared from livers of various species

SummaryThe velocity of hydrolysis of some acetanilide derivatives by guinea pig liver microsomes was found to be proportional to the microsome content of the suspension.Several extractions of the homogenate prepared from the livers of various species were needed for extracting most of the activity located in the soluble and the microsomal fraction.Acetanilide, p-acetaminophenol, phenacetin, and a ring-substituted phenacetin derivative (compound IX) were used as substrates in measuring the hydrolytic activity in the microsomal and soluble fraction from liver. The ratio between these activities was found to vary widely with the substrate and the species (rabbit, guinea pig, dog, and cat) used. The soluble fractions of all species hydrolyzed acetanilide more rapidly than the microsomes, and the microsomes were more active than the soluble fractions in hydrolyzing the ring-substituted phenacetin derivative.In a study of the hydrolysis of acetanilide and 12 derivatives by the microsomes prepared from the livers of rabbits, dogs, and guinea pigs the replacement of the N-acetyl residue in phenacetin by α-dimethylamino-β-hydroxybutyric acid was found to decrease the rate of hydrolysis. Substitution of an acetyl, propionyl, or butyryl residue in m-position to the amino group of phenacetin increased the rate of hydrolysis.N-methyl phenacetin was hydrolyzed more slowly than phenacetin by the soluble fractions prepared from guinea pigs, rabbits dogs and cats liver and by the microsomes except those from guinea pigs. The substitution of an N-methyl group in α-dimethylamino-β-hydroxybutyric acid phenetidide produced a compound which was found not to be hydrolyzed by microsomes or soluble fraction from the livers of the 4 species—or so slowly that it could not be detected in our experiments.

Subacute toxicity studies on pentachlorophenol (PCP), and the isomeric tetrachlorobenzenediols tetrachlorohydroquinone (TCH), tetrachlorocatechol (TCC), and tetrachlororesorcinol (TCR)

The toxicity of pure pentachlorophenol (PCP), tetrachlorohydroquinone (TCH), tetrachlorocatechol (TCC), and tetrachlororesorcinol (TCR), was examined in a short‐term study with female rats for 28 days. The substances were administered orally in doses of 0.2mMol/kg body wt×day, corresponding to 53.27 mg PCP, respectively 49.58 mg tetrachlorobenzenediol per kg body wt and day. The treatment had no effect on growth. Changes in relative liver weight, hematological parameters, and cell alterations in liver were only found in rats dosed with PCP.

Die Fungizide Hexachlorbenzol und Pentachlornitrobenzol und ihre Stoffwechselwege

Die Kenntnis biochemischer Veranderungen von lipophilen korperfremden Stoffen ist hinsichtlich deren Elimination aus dem Organismus, sowie bei Uberlegungen zur Voraussage toxischer, insbesondere carcinogener Wirkungen von vorrangiger Bedeutung