Studies on the mechanism of urotoxic effects of N,N'-dimethylaminopropionitrile in rats and mice. 1. Biochemical and morphologic characterization of the injury and its relationship to metabolism.
N,N'-Dimethylaminopropionitrile (DMAPN), a major component of the NIAX catalyst ESN, is known to cause urinary bladder dysfunction in exposed workers. In order to investigate the mechanism of DMAPN toxicity, we carried out time-course (0-72 h) and dose-response (175-700 mg/kg) studies on the effects of DMAPN in rats and mice. Treated animals exhibited several signs of toxicity including loss of body weight, reduced water consumption, and bladder urine retention, as well as bladder injury. DMAPN-induced bladder injury was characterized by distended bladders with marked diffuse submucosal and subserosal edema, petechial hemorrhage, and multifocal perivascular inflammatory infiltrates. The qualitative and quantitative analysis of urine indicated hypoosmolality, aciduria, hematuria, proteinuria, and oliguria. Elevated levels of creatinine and urea levels in plasma were indicative of renal dysfunction. Within hours following DMAPN administration, the animals exhibited a significant increase in urinary retention that resolved between 60 and 72 h. Rats excreted about 44% of the administered DMAPN dose unchanged in the urine, while mice excreted only about 6% of the dose. Commercially available DMAPN metabolites, administered by gavage, produced toxic effects less adverse than DMAPN. The biochemical effects of DMAPN included depletion of glutathione and increased lipid peroxidation in target organs, including urinary bladder and kidney. These studies indicate that there are species differences in DMAPN toxicity. The differences may be due to differences in the formation of reactive metabolic intermediates of DMAPN.
Mumtaz
M M
MM
Department of Pathology, University of Texas Medical Branch, Galveston 77550.
Farooqui
M Y
MY
Ghanayem
B I
BI
Rajaraman
S
S
Frankenberg
L
L
Ahmed
A E
AE
D000629:Aminopropionitrile / Q000031:analogs & derivatives* / Q000633:toxicity / Q000652:urine; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D005978:Glutathione / Q000032:analysis; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014508:Urea / Q000652:urine; D001743:Urinary Bladder / Q000187:drug effects*; D016055:Urinary Retention / Q000139:chemically induced; D014556:Urine / Q000737:chemistry
D000629:Aminopropionitrile; C019348:dimethylaminopropionitrile; D014508:Urea; D003404:Creatinine; D005978:Glutathione