Oxidation of 1,8-Cineole, the Monoterpene Cyclic Ether Originated From Eucalyptus Polybractea, by Cytochrome P450 3A Enzymes in Rat and Human Liver Microsomes

• Published in: Drug metabolism and disposition Vol. 29; no. 2; pp. 200 - 205
• Main Authors: MIYAZAWA, Mitsuo, SHINDO, Masaki, SHIMADA, Tsutomu
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.02.2001
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases; Baculoviridae - genetics; Biological and medical sciences; Cyclohexanols; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Enzyme Induction - drug effects; General pharmacology; Humans; Hydroxylation; Isoenzymes - biosynthesis; Isoenzymes - genetics; Isoenzymes - metabolism; Male; Medical sciences; Menthol - analogs & derivatives; Menthol - metabolism; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Monoterpenes; Moths - virology; Oxidation-Reduction; Oxidoreductases, N-Demethylating - biosynthesis; Oxidoreductases, N-Demethylating - metabolism; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Terpenes; Human; Rat; Digestive system; Pharmacognosy; Cytochrome P450; Liver; Rodentia; Metabolism; In vitro; Medicinal plant; Eucalyptol; Eucalyptus; Vertebrata; Mammalia; Dicotyledones; Animal; Angiospermae; Plant origin; Myrtaceae; Monoterpene; Spermatophyta; Essential oil; Oxidation
• ISSN: 0090-9556; 1521-009X

1,8-Cineole, the monoterpene cyclic ether known as eucalyptol, is one of the components in essential oils from Eucalyptus polybractea . We investigated the metabolism of 1,8-cineole by liver microsomes of rats and humans and by recombinant cytochrome P450 (P450 or CYP) enzymes in insect cells in which human P450 and NADPH-P450 reductase cDNAs had been introduced. 1,8-Cineole was found to be oxidized at high rates to 2- exo -hydroxy-1,8-cineole by rat and human liver microsomal P450 enzymes. In rats, pregenolone-16α-carbonitrile (PCN) and phenobarbital induced the 1,8-cineole 2-hydroxylation activities by liver microsomes. Several lines of evidence suggested that CYP3A4 is a major enzyme involved in the oxidation of 1,8-cineole by human liver microsomes: 1) 1,8-cineole 2-hydroxylation activities by liver microsomes were inhibited very significantly by ketoconazole, a CYP3A inhibitor, and anti-CYP3A4 immunoglobulin G; 2) there was a good correlation between CYP3A4 contents and 1,8-cineole 2-hydroxylation activities in liver microsomes of eighteen human samples; and 3) of various recombinant human P450 enzymes examined, CYP3A4 had the highest activities for 1,8-cineole 2-hydroxylation; the rate catalyzed by CYP3A5 was about one-fourth of that catalyzed by CYP3A4. Kinetic analysis showed that K m and V max values for the oxidation of 1,8-cineole by liver microsomes of human sample HL-104 and rats treated with PCN were 50 μM and 91 nmol/min/nmol P450 and 20 μM and 12 nmol/min/nmol P450, respectively. The rates observed using human liver microsomes and recombinant CYP3A4 were very high among other CYP3A4 substrates reported so far. These results suggest that 1,8-cineole, a monoterpenoid present in nature, is one of the effective substrates for CYP3A enzymes in rat and human liver microsomes.