Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-4503A in the mouse.
A higher level of cytochrome P-450 (P450)-dependent ethylmorphine (EM) N-demethylase activity was observed in hepatic microsomes from mice fed a natural-ingredient diet ("crude diet") than in those from mice fed a semi-purified diet ("purified diet"). This led to the testing of individual ingredients of the crude diet as inducers of the P-450 system. Brewers yeast proved to be the most significant inductive component of the crude diet. Further investigation revealed that hop components (lupulones) absorbed on yeast during the brewing process were responsible for the induction of the P-450 system. The induction of P-450 and several P-450-dependent monooxygenase activities (EM N-demethylation, aniline hydroxylation, benzo[a]pyrene hydroxylation) by colupulone with respect to dose and time course were investigated. The very large increase in EM N-demethylase activity elicited by colupulone suggested that P-4503A had been induced. Western blot technology verified this speculation. Western blot analysis of microsomal protein from mice fed hops, brewers yeast, or the residue of a hexane extract of hops supported the conclusion that all of these substances induced P-4503A. These substances were also relatively good inducers of P-4502B, but not as inductive of this isozyme as the crude diet. This is interpreted to mean that not all of the inductive properties of the crude diet are due to hop components. These studies question the use of crude commercial diets in studies of P-450 systems. They may also challenge some current definitions of "constitutive" and "induced" P-450s.
Department of Pharmacology, School of Medicine, Minneapolis, MN.
G J
GJ
Mannering
J A
JA
Shoeman
L B
LB
Deloria
D000818:Animals; D015153:Blotting, Western; D003512:Cyclohexanones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D005037:Ethylmorphine-N-Demethylase / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*
D003512:Cyclohexanones; C075356:colupulone; D003577:Cytochrome P-450 Enzyme System; D005037:Ethylmorphine-N-Demethylase