Binding of δ9‐tetrahydrocannabinol and diazepam to human serum albumin

Abstract

Cannabis is the most commonly used illicit drug worldwide. Cannabis users also appear to use other psychoactive drugs more frequently than noncannabis users. Here, Δ9‐ tetrahydrocannabinol (THC) and diazepam binding to human serum albumin (HSA) and HSA‐heme is reported. THC binds to two different binding sites of HSA (Kd1 ≤ 10−7 M and Kd2= 10−3 M) without affecting diazepam binding (Kd = 1.2 × 10−5 M). THC binding to the high‐affinity site accounts for the low free fraction of the drug in plasma. Moreover, THC increases the affinity of heme for HSA. Accordingly, the affinity of THC for HSA‐heme is higher than that for HSA. THC could bind to FA2 and FA7 sites, as substantiated by docking simulations; nevertheless, the observed allosteric effect(s) suggests that the primary binding site of THC is the FA2 cleft that positively modulates heme affinity. Possibly, the HSA conformational transition(s) induced by THC binding could account for drug delivery to the liver through receptor‐ mediated endocytosis. © 2011 IUBMB IUBMB Life, 63(6): 446–451, 2011

Pseudo-enzymatic hydrolysis of 4-nitrophenyl acetate by human serum albumin: pH-dependence of rates of individual steps

“…The value of K I here determined agrees with that reported previously [17,21]. These data agree with the view that Tyr411 located at the FA3-FA4 cleft [18] is the primary esterase site for the HSA-catalyzed hydrolysis of NphOAc [8,13].…”

Human serum albumin: From bench to bedside

“…Remarkably, heme-Fe binding confers to HSA globin-like spectroscopic and reactivity properties, thus providing a suitable tool to investigate allosteric and competitive properties (Antonini and Brunori, 1971;Bolognesi et al, 1997;Carter et al, 1999;Grinberg et al, 1999;Yamasaki et al, 1999;Komatsu et al, 2000;Mattu et al, 2001;Monzani et al, 2001Monzani et al, , 2002Fasano et al, 2002Fasano et al, , 2005Kamal and Behere, 2002;Komatsu et al, 2004bKomatsu et al, , 2005aAscenzi et al, , 2009aAscenzi et al, ,b, 2010aAscenzi et al, , 2010cAscenzi et al, , 2011aTsuchida et al, 2009;di Masi et al, 2011;Cao et al, 2011). The effects arising from heme-Fe binding to HSA might have some role in the regulation of biological functions.…”

“…This effect is not observed for short FAs (e.g., octanoate) that preferably bind to the FA3-FA4 site without inducing HSA allosteric rearrangement(s) . On this ground, FA2 ligands such as nevirapine, D9-tetrahydrocannabinol, and ibuprofen (binding to FA2 as the third, low-affinity site) consistently improve the hemeFe(III) affinity for HSA by one order of magnitude and affect heme-Fe-based spectroscopic and reactivity properties Fanali et al, 2011).…”

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

“…Male WT and LKO mice 5-7 mo. old were maintained, housed, and fed as described above and primary hepatocytes isolated as described earlier (32)(33)(34). Briefly, mice were euthanized by CO 2 asphyxiation, livers excised, and perfused with Buffer A [10 mM HEPES, pH 7.4 in calcium/magnesium-free Hank's buffered saline solution (HBSS), gentamycin sulfate (1 mg/ml medium), and 0.5 mM EGTA].…”