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

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Abstract
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 μmol/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 As3+-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 μmol∙kg−1∙day−1for 2 days, s.c.) had 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 activity (i.e., significant increase of P450 1A1 catalyzed activity but not 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.Key words: microsomal cytochrome P450, arsenite, oxidative stress, induction, liver, lung, kidney, monooxygenase activity.