Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite.

Nair, PC; Gillani, TB; Rawling, T; Murray, M

Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite.

Nair, PC Gillani, TB Rawling, T

Murray, M

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: Chemico-biological interactions, 2021, 338, pp. 109401
Issue Date:: 2021-02-05

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Field	Value	Language
dc.contributor.author	Nair, PC
dc.contributor.author	Gillani, TB
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Murray, M
dc.date.accessioned	2021-03-01T04:20:02Z
dc.date.available	2021-01-31
dc.date.available	2021-03-01T04:20:02Z
dc.date.issued	2021-02-05
dc.identifier.citation	Chemico-biological interactions, 2021, 338, pp. 109401
dc.identifier.issn	0009-2797
dc.identifier.issn	1872-7786
dc.identifier.uri	http://hdl.handle.net/10453/146559
dc.description.abstract	The tyrosine kinase inhibitor sorafenib (SOR) is being used increasingly in combination with other anticancer agents like paclitaxel, but this increases the potential for drug toxicity. SOR inhibits several human CYPs, including CYP2C8, which is a major enzyme in the elimination of oncology drugs like paclitaxel and imatinib. It has been reported that CYP2C8 inhibition by SOR in human liver microsomes is potentiated by NADPH-dependent biotransformation. This implicates a SOR metabolite in enhanced inhibition, although the identity of that metabolite is presently unclear. The present study evaluated the capacity of the major N-oxide metabolite of SOR (SNO) to inhibit CYP2C8-dependent paclitaxel 6α-hydroxylation. The IC<sub>50</sub> of SNO against CYP2C8 activity was found to be 3.7-fold lower than that for the parent drug (14 μM versus 51 μM). In molecular docking studies, both SOR and SNO interacted with active site residues in CYP2C8, but four additional major hydrogen and halogen bonding interactions were identified between SNO and amino acids in the B-B' loop region and helixes F' and I that comprise the catalytic region of the enzyme. In contrast, the binding of both SOR and SNO to active site residues in the closely related human CYP2C9 enzyme was similar, as were the IC<sub>50</sub>s determined against CYP2C9-mediated losartan oxidation. These findings suggest that the active metabolite SNO could impair the elimination of coadministered drugs that are substrates for CYP2C8, and mediate toxic adverse events, perhaps in those individuals in whom SNO is formed extensively.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation.ispartof	Chemico-biological interactions
dc.relation.isbasedon	10.1016/j.cbi.2021.109401
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	0601 Biochemistry and Cell Biology
dc.subject.classification	Toxicology
dc.title	Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite.
dc.type	Journal Article
utslib.citation.volume	338
utslib.location.activity	Ireland
utslib.for	0601 Biochemistry and Cell Biology
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	recently_added	*
dc.date.updated	2021-03-01T04:20:00Z
pubs.publication-status	Published
pubs.volume	338

Abstract:

The tyrosine kinase inhibitor sorafenib (SOR) is being used increasingly in combination with other anticancer agents like paclitaxel, but this increases the potential for drug toxicity. SOR inhibits several human CYPs, including CYP2C8, which is a major enzyme in the elimination of oncology drugs like paclitaxel and imatinib. It has been reported that CYP2C8 inhibition by SOR in human liver microsomes is potentiated by NADPH-dependent biotransformation. This implicates a SOR metabolite in enhanced inhibition, although the identity of that metabolite is presently unclear. The present study evaluated the capacity of the major N-oxide metabolite of SOR (SNO) to inhibit CYP2C8-dependent paclitaxel 6α-hydroxylation. The IC₅₀ of SNO against CYP2C8 activity was found to be 3.7-fold lower than that for the parent drug (14 μM versus 51 μM). In molecular docking studies, both SOR and SNO interacted with active site residues in CYP2C8, but four additional major hydrogen and halogen bonding interactions were identified between SNO and amino acids in the B-B' loop region and helixes F' and I that comprise the catalytic region of the enzyme. In contrast, the binding of both SOR and SNO to active site residues in the closely related human CYP2C9 enzyme was similar, as were the IC₅₀s determined against CYP2C9-mediated losartan oxidation. These findings suggest that the active metabolite SNO could impair the elimination of coadministered drugs that are substrates for CYP2C8, and mediate toxic adverse events, perhaps in those individuals in whom SNO is formed extensively.

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http://hdl.handle.net/10453/146559