Characterization of methemoglobin formation induced by 3,5-dichloroaniline, 4-amino-2,6-dichlorophenol and 3,5-dichlorophenylhydroxylamine.
3,5-Dichloroaniline is an intermediate in the production of certain fungicides. This study characterized the capacity of 3,5-dichloroaniline and two putative metabolites to induce methemoglobin formation. In vivo intraperitoneal (i.p.) administration of 0.8 mmol/kg 3,5-dichloroaniline resulted in elevated (P < 0.05) methemoglobin levels at 2 and 4 h after injection and returned to control values within 8 h. In vitro methemoglobin generation was monitored in washed erythrocytes incubated for 60 min at 37 degrees C with 4 and 8 mM 3,5-dichloroaniline. Methemoglobin generation in vitro was higher (P < 0.05) than control values in erythrocytes incubated for 30 min with 0.2-0.6 mM 4-amino-2,6-dichlorophenol or 5-100 microM 3,5-dichlorophenylhydroxylamine. The in vitro methemoglobin generating capacity in decreasing order was: 3,5-dichlorophenylhydroxylamine > 4-amino-2,6-dichlorophenol > > 3,5-dichloroaniline. The results of the in vitro studies further indicated that none of the compounds tested induced lipid peroxidation. Erythrocytes incubated with 5-100 microM 3,5-dichlorophenylhydroxylamine in vitro were associated with depletion of glutathione. These results indicated that: (a) 3,5-dichloroaniline and its metabolites can induce methemoglobin formation; (b) the N-hydroxy metabolite was the most potent inducer of hemoglobin oxidation and (c) glutathione depletion was associated with methemoglobin formation by 3,5-dichlorophenylhydroxylamine.
Valentovic
M A
MA
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25704-9388, USA. valentov@marshall.edu
Rogers
B A
BA
Meadows
M K
MK
Conner
J T
JT
Williams
E
E
Hong
S K
SK
Rankin
G O
GO
D000814:Aniline Compounds / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002733:Chlorophenols / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000097:blood; D006898:Hydroxylamines / Q000633:toxicity*; D015227:Lipid Peroxidation; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis*; D008708:Methemoglobinemia / Q000139:chemically induced*; D010080:Oxazoles; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
C104897:3,5-dichlorophenylhydroxylamine; D000814:Aniline Compounds; D002733:Chlorophenols; D006898:Hydroxylamines; D010080:Oxazoles; C088160:4-amino-2,6-dichlorophenol; C037268:dichlozolinate; D008706:Methemoglobin; D005978:Glutathione; C037267:3,5-dichloroaniline