Publications

We studied the relationship between duration and concentration of exposure in SO2-induced bronchoconstriction in 8 asthmatic subjects. On separate days, we administered SO2 in humidified air through a mouthpiece at 2 concentrations (0.5 and 1.0 ppm) for 3 time periods (1, 3, and 5 min) during eucapnic hyperpnea (60 L/min). Humidified air was administered for 5 min as a control. Bronchoconstriction was assessed by measurement of specific airway resistance (SRaw). The magnitude of the bronchoconstrictor response to both concentrations of SO2 increased progressively over the 3 time periods studied. The mean (+/- SE) increase in SRaw (in L x cm H2O/L/s) and percent increase above baseline (in parentheses) after each exposure to SO2 were as follows: 2.5 +/- 0.3 (34%) after 0.5 ppm for 1 min; 7.5 +/- 4.7 (93%) after 1.0 ppm for 1 min; 13 +/- 3.2 (173%) after 0.5 ppm for 3 min; 31.4 +/- 7.4 (395%) after 1.0 ppm for 3 min; 19.6 +/- 4.0 (234%) after 0.5 ppm for 5 min; 44.1 +/- 9.8 (580%) after 1.0 ppm for 5 min; 3.5 +/- 1.5 (46%) after humidified air for 5 min. For the group, the increases in SRaw caused by inhalation of both concentrations of SO2 for 1 min were small. However, 2 of 8 subjects did develop large increases in SRaw and chest tightness after inhalation of 1.0 ppm for 1 min. Seven of 8 subjects developed wheezing, chest tightness, or dyspnea and used an inhaled bronchodilator after inhalation of 0.5 ppm for 3 and 5 min and 1.0 ppm for 3 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-1,4-dihydropyridine (DDEP) (a structural analog of the dihydropyridine Ca2+ antagonists) to untreated, phenobarbital-, or dexamethasone-pretreated rats results in time-dependent losses of hepatic cytochrome P-450 content. Functional markers for various cytochrome P-450 isozymes have permitted the identification of P-450h, P-450 PB-1/k, and P-450p as the isozymes inactivated preferentially by the drug. DDEP-mediated cytochrome P-450 destruction may be reproduced in vitro, is most prominent after pretreatment of rats with dexamethasone, pregnenolone 16 alpha-carbonitrile or phenobarbital, and is blocked by triacetyloleandomycin. These findings together with the observation that DDEP markedly inactivates hepatic 2 beta- and 6 beta-testosterone hydroxylase and erythromycin N-demethylase tend to indict the steroid-inducible P-450p isozyme as a key protagonist in this event. The precise mechanism of such DDEP-mediated P-450p heme destruction is unclear, but involves prosthetic heme alkylation of the apocytochrome at its active site in what appears to be a novel mechanism-based "suicide" inactivation. Such inactivation appears to involve fragmentation of the heme to reactive metabolites that irreversibly bind to the protein, but the chemical structure of the heme-protein adducts is yet to be established. Intriguingly, such DDEP-mediated P-450p destruction in vivo also results in accelerated loss of immunochemically detectable apocytochrome P-450p. It remains to be determined whether or not this loss is due to enhanced proteolysis triggered by the structural modification of the apocytochrome.