THE SITE OF GENERAL-ANESTHESIA AND CYTOCHROME-P450 OXYGENASES - SIMILARITIES DEFINED BY STRAIGHT-CHAIN AND CYCLIC ALCOHOLS

1 General anaesthetics disrupt normal cell receptivity and responsiven ess while sparing vital respiratory processes. Ultimate elucidation of the molecular basis of general anaesthesia presumes the identificatio n of one or more subcellular components with appropriate sensitivity t o the entire array of anaesthetics. 2 Previously, we showed the univer sal cellular enzymes, cytochrome P450 mono-oxygenases, to be sensitive at relevant concentrations to all anaesthetics tested. The potential significance of P450 inhibition by anaesthetics resides in the contrib ution of this enzyme family. in conjunction with that of cyclo-oxygena ses and lipoxygenases, to the generation from arachidonic acid of lipi d second messengers, the eicosanoids. 3 We have shown that P450 enzyme s model the site of general anaesthesia in the tadpole with respect to (a) an absolute sensitivity to increasing chain-length series of flex ible, straight chain primary and secondary alcohols and straight chain diols, (b) an absolute sensitivity to increasing molecular weight ser ies of rigid cyclic alkanols and cyclic alkanemethanols, (c) the point s of abrupt change and of reversal (cut-off) in the linear relationshi p between increasing anaesthetic potency with increasing carbon chain length, and (d) non-differentiation between secondary alkanol enantiom ers. These findings reveal the P450 enzyme family as the most relevant biomolecular counterpart of the site of general anaesthesia, thus far identified.