The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Validation of Bupropion Hydroxylation as a Selective Marker of Human Cytochrome P450 2B6 Catalytic Activity
Abstract
The purpose of this study was to establish bupropion (BUP) hydroxylation as a selective in vitro marker of cytochrome P450 (CYP) 2B6 catalytic activity. Among a panel of 16 human liver microsomes (HLMs), BUP hydroxylase activity varied 80-fold when assayed at 500 microM substrate and significantly correlated with CYP2B6 blotting density (r(2) = 0.99) and S-mephenytoin N-demethylase activity (r(2) = 0.98). Kinetic analysis of BUP hydroxylation was performed in a subset of seven HLMs representative of the 80-fold range in activity. Sigmoidal kinetics suggestive of allosteric activation was observed in five HLMs exhibiting low or high activity; the mean apparent K(m) for BUP hydroxylation in these HLMs (130 microM) was similar to the K(m) for cDNA-expressed CYP2B6 (156 microM). Nonsaturable, biphasic kinetics was observed in two HLMs exhibiting low activity. Among a panel of cDNA-expressed P450 isoforms, CYP2B6 and CYP2E1 demonstrated the highest rates of BUP hydroxylation at 12 mM BUP (7.0 and 2.4 pmol/min/pmol of P450, respectively). The relative contributions of CYP2B6 and CYP2E1 to BUP hydroxylation were estimated by using immunoinhibitory monoclonal antibodies (MAB) to these enzymes. MAB-2B6 produced 88% maximum inhibition of BUP hydroxylation when assayed at 12 mM BUP in a high activity HLM, whereas MAB-2E1 produced 81% maximum inhibition in a low activity HLM. However, negligible inhibition by MAB-2E1 was observed when low and high activity HLMs were assayed at 500 microM BUP. These results demonstrate selectivity of BUP hydroxylation for CYP2B6 at 500 microM BUP, thereby validating its use as a diagnostic in vitro marker of CYP2B6 catalytic activity.
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Cited by
Zanger, U. M., & Schwab, M. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.12.007 · Cited by 4,169
Microscale culture of human liver cells for drug development
Khetani, S. R., & Bhatia, S. N. (2008) · Nature Biotechnology · doi:10.1038/nbt1361 · Cited by 1,219
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Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation
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Metadata
- Authors
- Faucette, S. R., Hawke, R. L., Lecluyse, E. L., Shord, S. S., Yan, B., Laethem, R. M., & Lindley, C. M.
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 28
- Issue
- 10
- Pages
- 1222-1230
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2108430406
- Cited by
- 353
- References
- 25
- FWCI
- 8.44
- Type
- journal article
- Language
- en
- Open access
- closed
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- Faucette, S. R., Hawke, R. L., Lecluyse, E. L., Shord, S. S., Yan, B., Laethem, R. M., & Lindley, C. M. (2000). Validation of Bupropion Hydroxylation as a Selective Marker of Human Cytochrome P450 2B6 Catalytic Activity. Drug Metabolism and Disposition. https://doi.org/10.1016/s0026-895x(24)12054-8
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