RT Journal Article
SR Electronic
T1 Oxidation Mechanism of 7-Hydroxy-Δ<sup>8</sup>-tetrahydrocannabinol and  8-Hydroxy-Δ<sup>9</sup>-tetrahydrocannabinol to the Corresponding  Ketones by CYP3A11
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1485
OP 1491
VO 29
IS 11
A1 Matsunaga, Tamihide
A1 Tanaka, Hiroyuki
A1 Higuchi, Shinsuke
A1 Shibayama, Kinya
A1 Kishi, Nobuyuki
A1 Watanabe, Kazuhito
A1 Yamamoto, Ikuo
YR 2001
UL http://dmd.aspetjournals.org/content/29/11/1485.abstract
AB A cDNA isolated from a C57BL/6 mouse liver cDNA library had the identical nucleotide sequence in coding region with the mouse CYP3A11, and the NH2-terminal sequence was also identical to that of cytochrome P450 (P450) MDX-B, a microsomal alcohol oxygenase. The COS-7 cells transfected with the CYP3A11 expression vector formed 7-oxo-Δ8-tetrahydrocannabinol (7-oxo-Δ8-THC) from 7α- and 7β-hydroxy-Δ8-THC. An immunologically related protein with P450 MDX-B was expressed in the COS-7 cell microsomes. The cell microsomes expressed CYP3A11; COS-3A11 catalyzed the oxidation of 7-hydroxy-Δ8-THC and 8-hydroxy-Δ9-THC to 7-oxo-Δ8-THC and 8-oxo-Δ9-THC, respectively, in a reconstituted system. 18O derived from atmospheric oxygen was incorporated into about 30% of the corresponding ketones formed from 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC by mouse hepatic microsomes, P450 MDX-B, and COS-3A11, although incorporation of the stable isotope into the oxidized metabolites from 7β-hydroxy-Δ8-THC and 8α-hydroxy-Δ9-THC was negligible. 18O, however, was not incorporated into 7-oxo-Δ8-THC formed from 7α-hydroxy-Δ8-THC by using cumene hydroperoxide instead of NADPH under 18O2. When18O-labeled 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC were incubated with above enzymes under air, about 30% of the ketones formed released 18O from a hydroxy group at the 7 and 8 positions in the course of the oxidation. These results suggest that 7α-hydroxy-Δ8-THC and 8β-hydroxy-Δ9-THC may be oxidized to the corresponding ketones by CYP3A11 via a gem-diol pathway. 7β-Hydroxy-Δ8-THC and 8α-hydroxy-Δ9-THC may be also converted to the ketones through a stereoselective dehydration of an enzyme-bound gem-diol rather than through a direct hydrogen extraction as a peroxy form of the enzyme. The American Society for Pharmacology and Experimental Therapeutics