Differential effects of coadministration of aminoacetonitrile on immunosuppression and hepatotoxicity produced by dimethylnitrosamine.
Aminoacetonitrile (AAN) has been reported to be a dimethylnitrosamine (DMN) demethylase inhibitor which prevents the metabolic activation of DMN to a hepatotoxin. The purpose of this investigation was to determine if AAN pretreatment, which ameliorates hepatotoxicity, would also prevent the immunotoxicity associated with DMN exposure. Female B6C3F1 mice were exposed to either 3 or 6 mg/kg of DMN (in saline) or saline i.p. for 7 consecutive days. The animals were also treated (i.p.) twice daily, 1 hr before and 6 hr after DMN exposure, with either, 10, 30 or 100 mg/kg of AAN (in saline) or saline. Mice were sensitized with sheep red blood cells i.v. on day 8. On day 12, body and organ weights were determined, serum chemistry and histopathology were evaluated and day 4 immunoglobulin M antibody response was measured. Hepatotoxicity caused by DMN, as reflected by an increase in body weight attributed to the production of ascites, a 485.7% increase in the serum glutamic pyruvic transaminase levels and histopathology was reversed by doses of AAN as low as 10 mg/kg. Conversely, doses of AAN as high as 100 mg/kg were unable to reverse the suppression of the antibody forming cells response to sheep red blood cells produced by DMN. The results of this investigation indicate that DMN-induced immunosuppression and hepatotoxicity can be separated and that an immunosuppressive metabolite of DMN is produced by an AAN-insensitive pathway.
Haggerty
H G
HG
Department of Pharmacology and Toxicology, Medical College of Virginia/Virginia Commonwealth University, Richmond.
Boise
L H
LH
Jordan
S D
SD
Holsapple
M P
MP
D000097:Acetonitriles / Q000494:pharmacology*; D000607:Aminoacetonitrile / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019392:Cytochrome P-450 CYP2E1; D004128:Dimethylnitrosamine / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D007165:Immunosuppression Therapy; D008099:Liver / Q000187:drug effects*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D013997:Time Factors
D000097:Acetonitriles; D000607:Aminoacetonitrile; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D004128:Dimethylnitrosamine