Metabolism of capsaicinoids: evidence for aliphatic hydroxylation and its pharmacological implications.
A new metabolic oxidation pathway of capsaicin (N-[(4-hydroxy-3-methoxyphenyl)-methyl]-8-methyl-(E)-6 -nonenamide), a major pungent and pharmacologically active principle of hot peppers, was investigated. Incubation of capsaicin with phenobarbital-induced rat liver postmitochondrial supernatant enriched with NADPH-generating system produced N-(4,5-dihydroxy-3-methoxybenzyl)-(E)-6 -nonenylamide and a more polar metabolite. The latter metabolite was spectrophotometrically and chromatographically identical to authentic omega-hydroxycapsaicin. This new metabolite was also detected in the urine of rabbits given capsaicin by gastric intubation. Other analogs of capsaicin, such as dihydrocapsaicin and nonivamide, also formed similar metabolites via aliphatic hydroxylation. When tested for antinociceptive activity as well as pungency, the above polar metabolites were found to be inactive while their parent compounds exhibited strong sensory effects. Capsaicin interacted irreversibly with heptic drug metabolizing enzymes, thereby inhibiting their activity as indicated by prolongation of pentobarbital sleeping time in rats. Such inhibition of drug metabolism was not observed with omega-hydroxycapsaicin. These findings suggest that metabolism of capsaicinoids via hydroxylation of their side chains plays an important role in the detoxification of these pharmacologically active substances.
Surh
Y J
YJ
College of Pharmacy, Seoul National University, Korea.
Ahn
S H
SH
Kim
K C
KC
Park
J B
JB
Sohn
Y W
YW
Lee
S S
SS
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000378:metabolism* / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008297:Male; D011817:Rabbits; D051381:Rats
D000700:Analgesics; D002211:Capsaicin