Δ9-Tetrahydrocannabinol and Its Major Metabolite Δ9-Tetrahydrocannabinol-11-oic Acid as 15-Lipoxygenase Inhibitors

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein, a major causal factor for atherosclerosis. Δ9-Tetrahydrocannabinol (Δ9-THC), a major component of marijuana, has suggested to suppress atherosclerosis. Although Δ9-THC seems to be attractive for the prevention of atherosclerosis, there is no information about whether or not 15-LOX isoform can be inhibited by Δ9-THC. In the present study, Δ9-THC was found to be a direct inhibitor for 15-LOX with an IC50 (50% inhibition concentration) value of 2.42 μM. Furthermore, Δ9-THC-11-oic acid, a major and nonpsychoactive metabolite of Δ9-THC, but not another Δ9-THC metabolite 11-OH-Δ9-THC (psychoactive), was revealed to inhibit 15-LOX. Taken together, it is suggested that Δ9-THC can abrogate atherosclerosis via direct inhibition of 15-LOX, and that Δ9-THC-11-oic acid is shown to be an “active metabolite” of Δ9-THC in this case.