Metabolism of Tetrahydrocannabinol by the Small Intestine

Abstract

The psychotomimetic effects of marihuana are due most probably to hydroxylated metabolites of tetrahydrocannabinol (Δ 9 THC), the major active alkaloid of the cannabis plant. Because ingested marihuana is psychotomimetic, we hypothesized that the human small intestinal mucosa is able to hydroxylate Δ 9 THC. Jejunal biopsies from normal volunteers were incubated in oxygenated flasks with purified 14 CΔ 9 THC (1.7 to 2.5 μg per ml) in a nutrient medium. Activity of fresh biopsies was compared with that of control boiled biopsies heated to 100 C for 3 min prior to their addition to the flask. After incubation and extraction, unchanged 14 C-Δ 9 THC and 14 C-Δ 9 THC metabolites were chromatographically separated and quantified. In six experiments, an average of 5.4% of added 14 C-Δ 9 THC was converted to polar metabolites in 2 hr. Metabolite formation was approximately linearly related to the duration of incubation and to tissue weight. The major (62%) polar metabolite of Δ 9 THC formed by human jejunal mucosa had the chromatographic mobility of 11-hydroxy THC. To define the route whereby absorbed Δ 9 THC and its metabolites leave the gut, we fed 3 H-oleic acid and 14 C-Δ 9 THC intraduodenally to 2 rats equipped with thoracic duct fistulae. Over 24 hr, 75% of the 3 H, but only 1.3% of the 14 C, were recovered in the lymph. Urine contained 12% of the fed 14 C. Portal absorption of 14 C-Δ 9 THC was demonstrated in 4 intact rats: 30 min after feeding 14 C-Δ 9 THC intraduodenally, portal blood contained 3 to 4 times as much 14 C as did simultaneously sampled inferior vena caval blood. About half of the portal 14 C consisted of polar metabolites of Δ 9 THC. Rat jejunal slices were also able to metabolize Δ 9 THC. We conclude that human small intestinal mucosa can hydroxylate Δ 9 THC. These cannabinoids are probably transported from the intestinal absorptive cells by the portal venous system.