Selective increase of rat lung cytochrome P450 1A1 dependent monooxygenase activity after acute sodium arsenite...

Arsenic is a known pulmonary, hepatic, and skin carcinogen in humans and a known inducer of stress proteins. Consequently, the ability of arsenite (As3+) to modulate isozyme-selective cytochrome P450 (P450) dependent monooxygenase activities was investigated in microsomes prepared from lung, liver, and kidney of male, adult Sprague-Dawley rats treated subcutaneously (s.c.) with sodium arsenite (75 mumol/kg body weight) 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 unchanged. Pulmonary ERF activity remained elevated for at least 48 h after As3+ treatment. In contrast, As3+ inhibited hepatic microsomal ERFD and PRFD activity by approximately 20 and 35%, respectively, 24 h after treatment. ERFD activity was also decreased in kidney microsomes of As(3+)-treated rats, but the inhibition was greater than in liver (50 vs. 35%) 24 h after injection. These effects are almost certainly not due 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, pretreatment of rats with Zn (153 mumol.kg-1.day-1 for 2 days, s.c.) had no effect on control or As(3+)-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 activity (i.e., significant increase of P450 1A1 catalyzed activity but not P450 2B catalyzed activity) in rat lung.(ABSTRACT TRUNCATED AT 250 WORDS)