Induction and inhibition of rat liver cytochrome(s) P-450 by an imidazole fungicide (prochloraz).
Prochloraz (1-[N-propyl-N-2(2,4,6-trichlorophenoxy) ethyl carbamoyl] imidazole) is an imidazole molecule widely used as a fungicide. This study reports the in vivo and in vitro effects of this compound on microsomal drug metabolising enzymes from rat liver. In vivo pretreatment of animals (250 mg/kg body wt for 3 days) with prochloraz elicited complex modifications. When animals were sacrificed 24 h after the last dose, an increase in total cytochrome P-450 was observed as well as an increase in catalytic activities towards benzphetamine, alkoxyresorufins and alkoxycoumarins. However, when animals were sacrificed 48 h after the last dose, a lower induction of 7-ethoxyresorufin O-deethylase and a higher induction of 7-pentoxyresorufin O-depentylase and 7-benzoxyresorufin O-debenzylase were found. Such results lead us to consider prochloraz as a "mixed inducer" of the hepatic cytochromes P-450. In vitro experiments were indicating a strong inhibition of 7-alkoxyresorufin O-dealkylase activities by prochloraz. The analysis of the CO-difference spectrum of cytochrome P-450 showed also tight binding of prochloraz to the haemoprotein in animals sacrificed 24 h but not 48 h after the last dose. Furthermore, prochloraz did not induce significantly the microsomal cytochrome P-450 IVA1-dependent 12-hydroxylation of lauric acid.
Laignelet
L
L
Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation, Laboratoire de Biochimie et Toxicologie Alimentaires, Dijon, France.
Narbonne
J F
JF
Lhuguenot
J C
JC
Riviere
J L
JL
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005659:Fungicides, Industrial / Q000378:metabolism / Q000633:toxicity*; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D010573:Pesticide Residues / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D005659:Fungicides, Industrial; D007093:Imidazoles; D010573:Pesticide Residues; D003577:Cytochrome P-450 Enzyme System; C045362:prochloraz