TY - JOUR
T1 - Differential Interactions of Selected Phytocannabinoids with Human CYP2D6 Polymorphisms
AU - Huff, Hannah C.
AU - Vasan, Archit
AU - Roy, Pritam
AU - Kaul, Aayush
AU - Tajkhorshid, Emad
AU - Das, Aditi
N1 - Funding Information:
This work was upported by National Institutes of Health Grants R01 GM1155884, R03 DA 04236502, and R21AT010761 to A.D. and R01 GM101048, U54 GM087519, and P41 GM104601 to E.T. All simulations were performed using XSEDE resources (MCA06N060 to E.T.).
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/9/21
Y1 - 2021/9/21
N2 - Cytochrome P450 2D6 (CYP2D6) is primarily expressed in the liver and in the central nervous system. It is known to be highly polymorphic in nature. It metabolizes several endogenous substrates such as anandamide (AEA). Concomitantly, it is involved in phase 1 metabolism of several antidepressants, antipsychotics, and other drugs. Research in the field of phytocannabinoids (pCBs) has recently accelerated owing to their legalization and increasing medicinal use for pain and inflammation. The primary component of cannabis is THC, which is well-known for its psychotropic effects. Since CYP2D6 is an important brain and liver P450 and is known to be inhibited by CBD, we investigated the interactions of four important highly prevalent CYP2D6 polymorphisms with selected phytocannabinoids (CBD, THC, CBDV, THCV, CBN, CBG, CBC, β-carophyllene) that are rapidly gaining popularity. We show that there is differential binding of CYP2D6*17 to pCBs as compared to WT CYP2D6. We also perform a more detailed comparison of WT and *17 CYP2D6, which reveals the possible regulation of AEA metabolism by CBD. Furthermore, we use molecular dynamics to delineate the mechanism of this binding, inhibition, and regulation. Taken together, we have found that the interactions of CYP2D6 with pCBs vary by polymorphism and by specific pCB class.
AB - Cytochrome P450 2D6 (CYP2D6) is primarily expressed in the liver and in the central nervous system. It is known to be highly polymorphic in nature. It metabolizes several endogenous substrates such as anandamide (AEA). Concomitantly, it is involved in phase 1 metabolism of several antidepressants, antipsychotics, and other drugs. Research in the field of phytocannabinoids (pCBs) has recently accelerated owing to their legalization and increasing medicinal use for pain and inflammation. The primary component of cannabis is THC, which is well-known for its psychotropic effects. Since CYP2D6 is an important brain and liver P450 and is known to be inhibited by CBD, we investigated the interactions of four important highly prevalent CYP2D6 polymorphisms with selected phytocannabinoids (CBD, THC, CBDV, THCV, CBN, CBG, CBC, β-carophyllene) that are rapidly gaining popularity. We show that there is differential binding of CYP2D6*17 to pCBs as compared to WT CYP2D6. We also perform a more detailed comparison of WT and *17 CYP2D6, which reveals the possible regulation of AEA metabolism by CBD. Furthermore, we use molecular dynamics to delineate the mechanism of this binding, inhibition, and regulation. Taken together, we have found that the interactions of CYP2D6 with pCBs vary by polymorphism and by specific pCB class.
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U2 - 10.1021/acs.biochem.1c00158
DO - 10.1021/acs.biochem.1c00158
M3 - Article
C2 - 34491040
SN - 0006-2960
VL - 60
SP - 2749
EP - 2760
JO - Biochemistry
JF - Biochemistry
IS - 37
ER -