SELECTIVE INCREASE OF RAT LUNG CYTOCHROME-P450 1A1 DEPENDENT MONOOXYGENASE ACTIVITY AFTER ACUTE SODIUM ARSENITE ADMINISTRATION

Arsenic is a known pulmonary, hepatic, and skin carcinogen in humans a nd a known inducer of stress proteins. Consequently, the ability of ar senite (As3+) to modulate isozyme-selective cytochrome P450 (P450) dep endent monooxygenase activities was investigated in microsomes prepare d from lung, liver, and kidney of male, adult Sprague-Dawley rats trea ted subcutaneously (s.c.) with sodium arsenite (75 mu mol/kg body weig ht) 24 h before death. In the lung, the activity of P450 1A1 catalyzed 7-ethoxyresorufin O-deethylation (ERFD) was markedly (approximately 5 -fold) increased in treated versus control rats, whereas the activity of P450 2B catalyzed 7-pentoxyresorufin O-depentylation (PRFD) was unc hanged. Pulmonary ERF activity remained elevated for at least 48 h aft er As3+ treatment. In contrast, As3+ inhibited hepatic microsomal ERFD and PRFD activity by approximately 20 and 35%, respectively, 24 h aft er treatment. ERFD activity was also decreased in kidney microsomes of As3+-treated rats, but the inhibition was greater than in liver (50 v s. 35%) 24 h after injection. These effects are almost certainly not d ue to a direct action of As3+ on P450-dependent catalysis, as in vitro addition of sodium As3+ at concentrations up to 1 mM had no effect on ERFD activity of control rat lung microsomes. In addition, pretreatme nt of rats with Zn (153 mu mol . kg(-1) . day(-1) for 2 days, s.c.) ha d no effect on control or As3+-mediated changes in P450-dependent ERFD activity of rat lung or kidney microsomes. These results demonstrate that As3+ is an isozyme-selective modulator of P450 monooxygenase acti vity (i.e., significant increase of P450 1A1 catalyzed activity but no t P450 2B catalyzed activity) in rat lung. In contrast, ERFD activity was significantly inhibited in both liver and kidney of the same As3+- treated rats.