The site of general anaesthesia and cytochrome P450 oxygenases: similarities defined by straight chain and cyclic alcohols.
1. General anaesthetics disrupt normal cell receptivity and responsiveness while sparing vital respiratory processes. Ultimate elucidation of the molecular basis of general anaesthesia presumes the identification of one or more subcellular components with appropriate sensitivity to the entire array of anaesthetics. 2. Previously, we showed the universal 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 contribution of this enzyme family, in conjunction with that of cyclo-oxygenases and lipoxygenases, to the generation from arachidonic acid of lipid second messengers, the eicosanoids. 3. We have shown that P450 enzymes model the site of general anaesthesia in the tadpole with respect to (a) an absolute sensitivity to increasing chain-length series of flexible, straight chain primary and secondary alcohols and straight chain diols, (b) an absolute sensitivity to increasing molecular weight series of rigid cyclic alkanols and cyclic alkanemethanols, (c) the points of abrupt change and of reversal (cut-off) in the linear relationship between increasing anaesthetic potency with increasing carbon chain length, and (d) non-differentiation between secondary alkanol enantiomers. These findings reveal the P450 enzyme family as the most relevant biomolecular counterpart of the site of general anaesthesia, thus far identified.
LaBella
F S
FS
Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine, Winnipeg, Canada.
Chen
Q M
QM
Stein
D
D
Queen
G
G
D000438:Alcohols / Q000494:pharmacology*; D000632:Aminopyrine / Q000378:metabolism; D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D006018:Glycols / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000438:Alcohols; D018681:Anesthetics, General; D002492:Central Nervous System Depressants; D065607:Cytochrome P-450 Enzyme Inhibitors; D006018:Glycols; D007527:Isoenzymes; D000632:Aminopyrine