Species and sex differences in the inhibitory action of the corticosteroid alclometasone dipropionate on the hepatic drug-metabolizing system.
The effect of successive administration of the corticosteroid alclometasone dipropionate (ACM) on the hepatic drug-metabolizing system was examined using male and female rats. Although some pharmacological changes such as increases in plasma enzyme activity, lipid level and protein concentration appeared similarly in ACM-treated male and female rats, the activities of 7-alkoxycoumarin O-dealkylase, especially the O-depropylation activity, decreased dose-dependently by ACM administration only in male rats. ACM did not affect the hepatic drug-metabolizing activity in female rats and mice of both sexes. Also, ACM did not inhibit androgen-independent aniline hydroxylase activity even in male rats. The time course of changes of the drug-metabolizing system in male rats showed a rapid decrease in cytochrome P-450 content and O-depropylation activity following successive treatments with ACM, but there was a slow onset in the decreases of the O-demethylation and O-deethylation activities of 7-alkoxycoumarin. When ACM was withdrawn, the O-demethylation and O-deethylation activities rapidly returned to their control levels, while recovery of the O-depropylation activity was slow. These results suggested that ACM inhibits the hepatic drug-metabolizing enzyme activity associated with a specific form(s) of androgen-dependent cytochrome P-450 in male rats.
Kanzakigawa Laboratory, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Y
Y
Nishibe
M
M
Hamataka
T
T
Hasegawa
J
J
Ikeuchi
T
T
Yoshizaki
A
A
Touchi
T
T
Matsubara
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008775:Methylprednisolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D006899:Mixed Function Oxygenases / Q000097:blood / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013045:Species Specificity; D013997:Time Factors
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C021137:alclometasone dipropionate; D008775:Methylprednisolone