Murine cytochrome P4503A is induced by 2-methyl-3-buten-2-ol, 3-methyl-1-pentyn-3-ol(meparfynol), and tert-amyl alcohol.
1. Colupulone, a constituent of hops, was shown to be a potent inducer of hepatic P4503A in mouse. The olefin, 2-methyl-3-buten-2-ol (RC = CH2), is formed from lupulones when hops are exposed to atmospheric hydroxyl radicals. This suggested the possibility that the same reaction may occur in vivo. The credibility of this hypothesis was enhanced when RC = CH2 was shown to induce P4503A in mouse. Ethylmorphine (EM) N-demethylation, a functional marker for P4503A, was also induced by RC = CH2. 2. 3-Methyl-1-pentyn-3-ol (RC identical to meparfynol), a sedative and close structural analogue of RC = CH2, also induced P4503A and EM N-demeythylation. Tert-amyl alcohol (RC-CH3), the saturated analogue of RC = CH2, was included in t he study with the expectation that it would serve as a negative control for the anticipated induction of P4503A by the other two alcohols. This proved not to be the case; RC-CH3 was about as active an inducer of P4503A as RC = CH2 and RC identical to CH. The possibility is considered that, like valproic acid, RC-CH3 is metabolized to an olefin by P450. 3. Hydroxylation of aniline and benzo[a]pyrene by hepatic microsomes from mice treated with the three alcohols were used as functional markers for the induction of P4502E and P4501A respectively. RC = CH2 at the two lowest levels of administration suppressed aniline hydroxylation but had no effect at the highest level. RC identical to CH was ineffective and RC-CH3 was moderately inductive at all three levels. Each of the three compounds were weak to moderate inducers of benzo[a]pyrene hydroxylation.
Mannering
G J
GJ
Department of Food Science and Nutrition, College of Agriculture, University of Minnesota, St Paul 55108, USA.
Shoeman
J A
JA
D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003512:Cyclohexanones / Q000494:pharmacology; D005036:Ethylmorphine / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D051379:Mice; D000439:Pentanols / Q000494:pharmacology*
D000814:Aniline Compounds; D003512:Cyclohexanones; D000439:Pentanols; C075356:colupulone; C032765:tert-amyl alcohol; C004347:methylpentynol; D005036:Ethylmorphine; C027250:3-hydroxy-3-methylbutene; C023650:aniline