Procainamide hydroxylamine lymphocyte toxicity--I. Evidence for participation by hemoglobin.
A number of lines of evidence suggest that the lupus-like symptoms associated with procainamide therapy may be caused by products of metabolic N-oxidation. In the present study, the perfusion of the isolated rat liver with a hemoglobin-free solution containing procainamide (100 microM) resulted in the rapid appearance of the N-oxidation metabolite procainamide hydroxylamine in the perfusate. Addition of procainamide hydroxylamine in vitro to whole rat blood (1-40 microM) resulted in a concentration-dependent loss of proliferative response among mononuclear cells isolated from the treated blood and cultured with mitogens (phytohemagglutinin, PHA-P: concanavalin A, Con A; and pokeweed mitogen, PWM), as well as a loss of viability. Similar effects on lymphocyte mitogen responsiveness were observed when procainamide hydroxylamine (1-40 microM) was added to rat whole splenic cell populations. Carbon monoxide or ascorbic acid pretreatment inhibited the toxicity of procainamide hydroxylamine to lymphocytes in whole blood, but only carbon monoxide pretreatment inhibited procainamide hydroxylamine-induced methemoglobin formation. These observations are consistent with the participation of hemoglobin in a redox cycle with procainamide hydroxylamine, generating products which are primarily responsible for its cytotoxicity in blood.
Roberts
S M
SM
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock.
Adams
L E
LE
Donovan-Brand
R
R
Budinsky
R
R
Skoulis
N P
NP
Zimmer
H
H
Hess
E V
EV
D000120:Acecainide / Q000633:toxicity; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006454:Hemoglobins / Q000502:physiology*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D008706:Methemoglobin / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011342:Procainamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism
D006454:Hemoglobins; D002248:Carbon Monoxide; D008706:Methemoglobin; D000120:Acecainide; C051948:procainamide 4-hydroxylamine; D011342:Procainamide; D001205:Ascorbic Acid; D013936:Thymidine