{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:22:36Z","timestamp":1792732956118,"version":"4.5.0"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute at the National Institutes of Health","doi-asserted-by":"publisher","award":["R01-CA269223"],"award-info":[{"award-number":["R01-CA269223"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008209","name":"University at Buffalo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008209","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Introduction: The use of \u03948-tetrahydrocannabinol (\u03948-THC) has become increasingly prevalent in the United States, but its metabolic pathways remain poorly characterized. This study aimed to identify the key enzymes responsible for the 11\u2032-hydroxylation of \u03948-THC, its primary metabolic pathway, and assess the effect of metabolizing enzyme genotype on this activity. Results: The intrinsic clearance of recombinant (r) CYP2C9 was &gt;6200\u2212fold higher than that observed for rCYP2C19, the only other tested CYP450 with detectable activity against \u03948-THC. The Km,u of rCYP2C9 (0.013 \u00b1 0.0032 \u00b5M) was comparable to that observed in human intestinal microsomes (0.0076 \u00b1 0.00067 \u00b5M), but it was substantially lower than that observed for human liver microsomes (0.73 \u00b1 0.065 \u00b5M). Inhibition of 11-OH-\u03948-THC formation in rCYP-overexpressing microsomes was observed when using CYP probe inhibitors (sulfaphenazole for CYP2C9 and tranylcypromine for CYP2C19). The intrinsic clearance was markedly reduced in CYP2C9 variant microsomes, with 20\u2212 to 60\u2212fold decreases observed for CYP2C9*2 (59 \u00b1 7.9 \u00b5L\u00b7min\u22121\u00b7mg\u22121 protein), CYP2C9*3 (34 \u00b1 3.6 \u00b5L\u00b7min\u22121\u00b7mg\u22121 protein), CYP2C9*8 (96 \u00b1 13 \u00b5L\u00b7min\u22121\u00b7mg\u22121 protein), and CYP2C9*9 (34 \u00b1 11 \u00b5L\u00b7min\u22121\u00b7mg\u22121 protein) as compared to wild-type CYP2C9*1 (6028 \u00b1 266 \u00b5L\u00b7min\u22121\u00b7mg\u22121 protein). Conclusions: Given that the expression of CYP2C9 is much higher than that of CYP2C19 in both human intestine and liver, these data suggest that CYP2C9 is the primary enzyme responsible for intestinal 11\u2032-hydroxylation of \u03948-THC and that other untested CYPs may be important in hepatic \u03948-THC hydroxylation. In addition, the reduced 11-OH-\u03948-THC formation activity observed with CYP2C9 variants (*2, *3, *8, *9) suggests interindividual variability in \u03948-THC disposition.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091149","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:39:24Z","timestamp":1789137564000},"page":"1149","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cytochrome P450-Catalyzed Hydroxylation of \u03948-Tetrahydrocannabinol and Implications for Pharmacogenetics"],"prefix":"10.3390","volume":"18","author":[{"given":"Mengqi","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Molecular Biosciences, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 160 Hayes Rd., Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Philip","family":"Lazarus","sequence":"additional","affiliation":[{"name":"Division of Molecular Biosciences, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 160 Hayes Rd., Buffalo, NY 14215, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"ref_1","first-page":"180","article-title":"Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting","volume":"42","author":"Bridgeman","year":"2017","journal-title":"P T"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1001\/jama.2024.0801","article-title":"The Public Health Challenge of \u03948-THC and Derived Psychoactive Cannabis Products","volume":"331","author":"Whitehill","year":"2024","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/02791072.2023.2200211","article-title":"Delta-8- and Delta-9-THC Use Frequency, Use Motives, and Mental Health Outcomes","volume":"56","author":"Pellicane","year":"2024","journal-title":"J. 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