Decrease in a constitutive form of cytochrome P-450 by macrolide antibiotics.
The effects of administration of macrolide antibiotics on cytochrome P-450 in liver microsomes of male rats were investigated. The macrolides tested were those with a 14-membered ring such as oleandomycin, troleandomycin, erythromycin and erythromycin estolate, and those with a 16-membered ring such as rokitamycin, leucomycin and josamycin. Cytochrome P-450-metabolite complex was detected with oleandomycin, troleandomycin, erythromycin and erythromycin estolate, whereas no such effect was observed with rokitamycin, leucomycin and josamycin. The content of uncomplexed cytochrome P-450 in liver microsomes remained unchanged with rokitamycin, leucomycin and josamycin, decreased with troleandomycin and oleandomycin, and increased with erythromycin and erythromycin estolate, indicating that oleandomycin, troleandomycin, erythromycin and erythromycin estolate also affect the amounts of other forms of cytochrome P-450. The administration of oleandomycin, troleandomycin, erythromycin and erythromycin estolate resulted in a dramatic decrease in the activities of testosterone 2 alpha- and 16 alpha-hydroxylases in liver microsomes. Supporting these results, a marked decrease (more than 75%) in the content of P-450-male, a major constitutive form of cytochrome P-450 in male rats, was noted with oleandomycin, troleandomycin, erythromycin and erythromycin estolate, while the decrease was rather small with rokitamycin and leucomycin. We conclude that the administration of the 14-membered ring macrolides may affect drug and steroid metabolism not only by formation of P-450-metabolite complex but also by decrease in the content of P-450-male.
Miura
T
T
Division of Analytical Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Iwasaki
M
M
Komori
M
M
Ohi
H
H
Kitada
M
M
Mitsui
H
H
Kamataki
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D065607:Cytochrome P-450 Enzyme Inhibitors; D007120:Immunochemistry; D066298:In Vitro Techniques; D018942:Macrolides; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018942:Macrolides; D011506:Proteins; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C022724:testosterone 7-alpha-hydroxylase, hamster; D009251:NADPH-Ferrihemoprotein Reductase