Metabolic activation of phenol by human myeloperoxidase and horseradish peroxidase.

The oxidation of phenol catalyzed by human myeloperoxidase and horseradish peroxidase resulted in extensive binding of phenol-derived metabolites to boiled rat liver protein. This binding paralleled closely the removal of phenol from the incubations and was inhibited from 83 to 99% by the addition of the antioxidants, ascorbate and glutathione, suggesting that metabolism and binding were occurring via a one-electron oxidation pathway. Metabolic studies employing both human myeloperoxidase and horseradish peroxidase resulted in the identification of 4,4'-biphenol and diphenoquinone as the principal identifiable metabolites. The addition of reduced glutathione to incubations containing horseradish peroxidase resulted in the formation of two conjugate species. These conjugate species were identified by fast atom bombardment mass spectrometry to be glutathione conjugates of diphenoquinone. The major gluthathione conjugate was identified as 3-(glutathion-S-yl)-4,4'-biphenol by NMR spectroscopy. These results suggest that the formation of highly reactive species through the peroxidase-mediated metabolism of phenol and other phenolic compounds could play an important role in the hematopoietic toxicity observed during chronic benzene exposure.

Reactive intermediates in pesticide metabolism: peracid oxidations as possible biomimetic models.

Reactive intermediates generated by metabolic epoxidation, N-oxidation and S-oxidation are often identical to those obtained on peracid oxidation as illustrated by studies with a variety of pesticides. Epoxidation reactions carried out metabolically or with peracids lead to transitory or unstable epoxychrysanthemic acid, epoxycyclopentenolone and epoxyfuran derivatives from pyrethroids, and geranyl-derived diepoxides and epoxydiols from juvenoids. N-Oxidation with microsomal oxidases or peracids activates hydroxylamine ether proinsecticides and dimethylphosphoramide and aminodiphenyl ether promutagens, but the peracid system is not always a suitable biomimetic model. Sulphoxidations with peracids appear to give the same reactive intermediates as those involved in metabolism of S-alkyl thiocarbamate and S-methyl-triazinone herbicides, S-chloroallyl promutagens, and S-propyl phosphorothiolate and phosphinyliminodithiolane proinsecticides.

A new pyrethroid insecticide with remarkable potency on nerve axons.

The analog of cis-tetramethrin with a 2,2-dimethyl-cyclopropyl replacement for the 2-methyl-1-propenyl group, i.e., "methanotetramethrin", is one of the most neuroactive compounds ever described. It is 10(3)- to greater then 10(5)-fold more potent than tetramethrin in inducing repetitive firing following stimulation in a cockroach cercal sensory nerve in vitro, and the repetitive firing is considerably more persistent. Also, it is more toxic to the cockroach and the housefly. The remarkable potency of methanotetramethrin, giving consistent repetitive firing in this nerve assay at 10(-18) M, and the speculation that it may undergo reversible covalent binding via Michael addition indicate that it could be a useful neurophysiological probe and candidate affinity label for the sodium channel.

Metabolism and toxicology of pyrethroids with dihalovinyl substituents.

Replacement of the photolabile and biodegradable isobutenyl substituent of pyrethroids with a dihalovinyl group often leads to improved insecticidal potency and enhanced photostability. This type of structural modification does not greatly alter the ease of detoxification in mammals since other sites in the molecule undergo metabolic attack. The available toxicological information on dihalovinyl pyrethroids indicates that they are suitable replacements for other insecticides with less favorable persistence and toxicological characteristics.

The metabolism of 4-chlorobiphenyl in the pig.

1-Chlorobiphenyl was administered retrocarotidly in a saline oil emulsion to anesthetized pigs. The urine obtained from the pigs 2 h after injection of the 4-chlorobiphenyl was analyzed for metabolites. Mass spectrometric analysis indicated the presence of a monohydroxylated species (M+ 204) and a dihydroxylated compound (M+ 220) and these were identified as 4'-chloro-4-biphenylol and 4'-chloro-3,4-biphenyldiol, respectively. Examination of the urine extracts from pigs 0.5, 1, and 2 h after administration of the 4-chlorobiphenyl indicated an increase in both urinary metabolites with time, however, neither compound was detected in the bile. Blood and organ samples were examined also for metabolites and the results clearly showed the presence of 4'-chloro-4-biphenylol in the blood, kidney, and liver and absence in the lung, brain, and heart. The diol was not observed in any of these samples.