Amyl, isobutyl, butyl and cyclohexyl nitrites are volatile chemicals, which are abused by inhalation. Abuse of nitrite inhalants is particularly widespread among homosexuals. Epidemiological studies have identified heavy nitrite abuse as a risk factor in AIDS and also in Kaposi's sarcoma (KS) in AIDS patients. Data, obtained in this laboratory, suggests that mouse inhalation of isobutyl nitrite at levels approximating the exposure of habitual abusers severely compromises both antibody and cell-mediated immune mechanisms. The immunodeficiency was shown to target accessory cell functions, including cytokine synthesis. The present study will investigate the mechanisms of nitrite inhalant toxicity. The reactivity of nitrite inhalants will be examined to determine if they directly or indirectly modify the activity of critical cellular constituents through nitration or disruption of iron-sulfur centers. The induction of DNA breakage and impairment of the respiratory chain, the Krebs cycle enzyme, aconitase, and the nuclear binding factor, NF-kappa B will be examined. Inhalant-induced changes in NF-kappa B on signal transduction will be studied. Since previous studies indicated that inhalation exposure to the nitrites enhanced the production, but not transcription of the cytokine, tumor necrosis factor-alpha (TNF-alpha), nitrite effects on post-transcriptional processing, such as a translational efficiency and processing will be examined.

R01DA006662

1991-06-01

2003-01-31