Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes.
Synthetic cannabinoids developed by chemical modification are believed to bind to cannabinoid receptors and cause neurological effects similar to cannabis; however, their effects on drug metabolizing enzymes are unknown. This study aimed to elucidate the effect of synthetic cannabinoids on cytochrome P450 1A activity. Naphthoylindole, a basic structure of the major synthetic cannabinoids, strongly inhibited CYP1A activity in a competitive manner; the apparent Ki value was 0.40 μM. The N-Alkylated derivatives of naphthoylindole, MAM-2201 and JWH-019, also inhibited CYP1A activity in a concentration-dependent manner; however, their inhibitory effects were weaker than naphthoylindole. An adamantylamidoindole derivative, STS-135, showed inhibition of CYP1A activity in a concentrationdependent manner, but the adamantoylindole derivatives, AB-001 and AM-1248, did not. A tetramethylcyclopropanoylindole derivative, UR-144, showed a weak inhibition of CYP1A activity at high concentrations. These results suggest that synthetic cannabinoids and their basic molecules are capable of inhibiting CYP1A enzymatic activity.
Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy.
Takashi
T
Ashino
Kanae
K
Hakukawa
Yuka
Y
Itoh
Satoshi
S
Numazawa
D000818:Animals; D001667:Binding, Competitive; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D013287:Illicit Drugs / Q000633:toxicity*; D008297:Male; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013329:Structure-Activity Relationship
D002186:Cannabinoids; D013287:Illicit Drugs; D043882:Receptors, Cannabinoid; D019363:Cytochrome P-450 CYP1A1