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 hydro xyl radicals. This suggested the possibility that the same reaction ma y occur in vivo. The credibility of this hypothesis was enhanced when RC=CH, was shown to induce P4503A in mouse. Ethylmorphine (EM) N-demet hylation, a functional marker for P4503A, was also induced by RC=CH2. 2. 3-Methyl-1-pentyn-3-ol (RC=CH, meparfynol), a sedative and close st ructural analogue of RC=C2(H), also induced P4503A and EM N-demethylat ion. Tert-amyl alcohol (RC-CH3), the saturated analogue of RC=CH2, was included in the study with the expectation that it would serve as a n egative control for the anticipated induction of P4503A by the other t wo alcohols. This proved not to be the case; RC-CH, was about as activ e an inducer of P4503A as RC=CH2 and RC=CH. The possibility is conside red that, like valproic acid, RC-CH3 is metabolized to an olefin by P4 50. 3. Hydroxylation of aniline and benzo[a]pyrene by hepatic microsom es from mice treated with the three alcohols were used as functional m arkers for the induction of P4502E and P4501A respectively. RC=CH2 at the two lowest levels of administration suppressed aniline hydroxylati on but had no effect at the highest level. RC=CH was ineffective and R C-CH3 was moderately inductive at all three levels. Each of the three compounds were weak to moderate inducers of benzo[a]pyrene hydroxylati on.