Effects of acute sodium arsenite administration on the pulmonary chemical metabolizing enzymes, cytochrome P-450 monooxygenase, NAD(P)H:quinone acceptor oxidoreductase and glutathione S-transferase in guinea pig: comparison with effects in liver and kidney.
Tissue specific changes in the cytochrome P-450 (P-450) monooxygenase system were observed following a single subcutaneous dose of sodium arsenite (75 mumol/kg), a known inducer of stress proteins. P-450 monooxygenase activities were assayed with several isozyme selective substrates; 7-ethoxyresorufin, 7-pentoxyresorufin, 4-aminobiphenyl and erythromycin. Both tissue selective and isozyme selective changes in monooxygenase activity were noted. For example, the rate of 4-aminobiphenyl N-hydroxylation (ABH) was increased by arsenite administration in lung but not in liver. Arsenite inhibited 7-ethoxyresorufin O-deethylation (ERF) in all tissues of control animals, but to a lesser extent in lung. However, increases of ERF activity occurred after arsenite treatment in lung of beta-naphthoflavone (beta NF)-treated guinea pigs whereas arsenite decreased ERF activities in the kidney and liver of these animals. These complex effects on ERF activity may in part be modulated by induction of heme oxygenase, whose activity was increased 2.5-3.5-fold in these organs by arsenite. The highest heme oxygenase activity was found in kidney with lower activities being present in liver and lung, respectively. These data are consistent with the decreased P-450 content observed in kidney and liver microsomes of arsenite treated guinea pigs. On the other hand there was either no change or a slight increase (about 2-fold) in the pulmonary microsomal P-450 content of these animals. A complex pattern of induction for the non-heme, Ah locus associated enzyme, NAD(P)H:quinone acceptor oxidoreductase (QOR) was also observed. With menadione as substrate arsenite treatment increased QOR activity in all tissues studied. However, with dichlorophenolindophenol (DCPIP) as substrate a significant arsenite effect was observed only in the kidney. Significant differences between the QOR substrates were also observed in beta NF-treated guinea pigs and control animals. Our results are consistent with the presence of more than one form of QOR in the guinea pig. Arsenite treatment also caused an increase in glutathione S-transferase activity, with 2,4-dinitro-1-chlorobenzene (DNCB) as substrate, of guinea pig kidney but not liver or lung.
Falkner
K C
KC
Department of Pharmacology & Toxicology, University of Western Ontario, London, Canada.
McCallum
G P
GP
Cherian
M G
MG
Bend
J R
JR
D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D018053:Arsenites; D001571:Benzoflavones / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006168:Guinea Pigs; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011808:Quinone Reductases / Q000378:metabolism*; D017670:Sodium Compounds; D019324:beta-Naphthoflavone
D018053:Arsenites; D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D017670:Sodium Compounds; C017947:sodium arsenite; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C027685:4-aminobiphenyl N-hydroxylase; D019363:Cytochrome P-450 CYP1A1; C041831:NADH dehydrogenase (quinone); D011808:Quinone Reductases; D005982:Glutathione Transferase; D001151:Arsenic