Routes of metabolism of [36Cl] ring-substituted monochloroacetanilides

Newell, Marjorie P.; Argus, Mary F.; Ray, Francis Earl

doi:10.1016/0006-2952(60)90005-8

Cited by 11 publications

(2 citation statements)

References 19 publications

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“…3,5-DCPHA was synthesized by reduction of 3,5-DCNB using hydrazine-palladium on carbon via the previously described method of Rondestvedt and Johnson [ 54 ] and purified as described by Valentovic et al [ 55 ]. Synthesis and purification of 3,5-DCAA was accomplished using the method of Newell et al [ 56 ] by reacting equal amounts of 3,5-dichloroaniline and acetic anhydride in the presence of sodium acetate. To prepare 2-A-4,6-DCP, 2,4-dichlorophenol was nitrated using the method of McMillan et al [ 29 , 57 ] followed by reduction of the nitro group to an amino group with sodium hydrosulfite in 10% aqueous sodium hydroxide according to Newell et al [ 56 ].…”

Section: Methodsmentioning

confidence: 99%

“…Synthesis and purification of 3,5-DCAA was accomplished using the method of Newell et al [56] by reacting equal amounts of 3,5-dichloroaniline and acetic anhydride in the presence of sodium acetate. To prepare 2-A-4,6-DCP, 2,4dichlorophenol was nitrated using the method of McMillan et al [29,57] followed by reduction of the nitro group to an amino group with sodium hydrosulfite in 10% aqueous sodium hydroxide according to Newell et al [56].…”

Section: Chemicalsmentioning

confidence: 99%

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Nephrotoxic Potential of Putative 3,5-Dichloroaniline (3,5-DCA) Metabolites and Biotransformation of 3,5-DCA in Isolated Kidney Cells from Fischer 344 Rats

Rankin

Racine

Valentovic

et al. 2020

IJMS

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The current study was designed to explore the in vitro nephrotoxic potential of four 3,5-dichloroaniline (3,5-DCA) metabolites (3,5-dichloroacetanilide, 3,5-DCAA; 3,5-dichlorophenylhydroxylamine, 3,5-DCPHA; 2-amino-4,6-dichlorophenol, 2-A-4,6-DCP; 3,5-dichloronitrobenzene, 3,5-DCNB) and to determine the renal metabolism of 3,5-DCA in vitro. In cytotoxicity testing, isolated kidney cells (IKC) from male Fischer 344 rats (~4 million/mL, 3 mL) were exposed to a metabolite (0–1.5 mM; up to 90 min) or vehicle. Of these metabolites, 3,5-DCPHA was the most potent nephrotoxicant, with 3,5-DCNB intermediate in nephrotoxic potential. 2-A-4,6-DCP and 3,5-DCAA were not cytotoxic. In separate experiments, 3,5-DCNB cytotoxicity was reduced by pretreating IKC with antioxidants and cytochrome P450, flavin monooxygenase and peroxidase inhibitors, while 3,5-DCPHA cytotoxicity was attenuated by two nucleophilic antioxidants (glutathione and N-acetyl-L-cysteine). Incubation of IKC with 3,5-DCA (0.5–1.0 mM, 90 min) produced only 3,5-DCAA and 3,5-DCNB as detectable metabolites. These data suggest that 3,5-DCNB and 3,5-DCPHA are potential nephrotoxic metabolites and may contribute to 3,5-DCA induced nephrotoxicity in vivo. In addition, the kidney can bioactivate 3,5-DCNB to toxic metabolites, and 3,5-DCPHA appears to generate reactive metabolites to contribute to 3,5-DCA nephrotoxicity. In vitro, N-oxidation of 3,5-DCA appears to be the primary mechanism of bioactivation of 3,5-DCA to nephrotoxic metabolites.

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Section: Methodsmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Nephrotoxic Potential of Putative 3,5-Dichloroaniline (3,5-DCA) Metabolites and Biotransformation of 3,5-DCA in Isolated Kidney Cells from Fischer 344 Rats

Rankin

Racine

Valentovic

et al. 2020

IJMS

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A theoretical study on the oxidative metabolism of 4‐chloroacetanilide by cytochrome P450: Alternative mechanisms for migration of 4‐substituents during enzymatic oxidation

Koymans

Menge

Kelder

et al. 1993

Recl. Trav. Chim. Pays‐Bas

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Abstract. The oxidative metabolism of 4-chloroacetanilide (4-CIAA. 1 ) by cytochrome P450 has been studied theoretically using ab-initio energy and spin-distribution calculations. A mechanism of oxidation for 4-CIAA is proposed which is in accordance with recent views on the mechanism of metabolic oxidation of substrates by cytochrome P450. An initial one-electron-oxidation step in the metabolic activation of 4-CIAA is suggested to be a hydrogen abstraction from nitrogen in the acetylamino side chain. Spin-delocalisation and subsequent radical recombination reactions between a hydroxyl radical and the reactive centres of the substrate radical can explain the formation of N-HO-and 2-HO-4-CIAA (4, 9), two known metabolites of 4-CIAA. Furthermore, the formation of a 2,5-cyclohexadien-1-imine intermediate (

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2-Amino-5-chlorophenol Toxicity in Renal Cortical Slices from Fischer 344 Rats: Effect of Antioxidants and Sulfhydryl Agents

Valentovic

Meadows

Harmon

et al. 1999

Toxicology and Applied Pharmacology

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Routes of metabolism of [36Cl] ring-substituted monochloroacetanilides

Cited by 11 publications

References 19 publications

Nephrotoxic Potential of Putative 3,5-Dichloroaniline (3,5-DCA) Metabolites and Biotransformation of 3,5-DCA in Isolated Kidney Cells from Fischer 344 Rats

Nephrotoxic Potential of Putative 3,5-Dichloroaniline (3,5-DCA) Metabolites and Biotransformation of 3,5-DCA in Isolated Kidney Cells from Fischer 344 Rats

A theoretical study on the oxidative metabolism of 4‐chloroacetanilide by cytochrome P450: Alternative mechanisms for migration of 4‐substituents during enzymatic oxidation

2-Amino-5-chlorophenol Toxicity in Renal Cortical Slices from Fischer 344 Rats: Effect of Antioxidants and Sulfhydryl Agents

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