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Sylvie KANDEL

Research Instructor, Ph.D.

Dr. Sylvie Kandel is a DMPK (Drug Metabolism & Pharmacokinetics) scientist focusing on the biotransformation of drugs by cytochrome P450 enzymes. Her Ph.D. work at the Institute of Molecular Biology of Plants (IBMP, Strasbourg) in France targeted plant cytochrome P450 enzymes and their involvement in cutin biosynthesis and plant defense. She then joined the Ortiz de Montellano lab at UCSF (San Francisco, USA) for post-doctoral training. There, she investigated mammalian P450 enzymes using nanodisc technology and collaborated on several projects including the assessment of cytochrome P450 CYP119 ligand binding dynamics using NMR spectroscopy. Through her industrial experiences at Sekisui XenoTech, LLC (Kansas City, KS) and Denali Therapeutics (San Francisco, CA), she applied her drug metabolism knowledge and analytical skills performing metabolite identification and structure elucidation studies of small molecule drug candidates to support drug development. Her last two academic positions at the University of Kansas, Medical Center (Kansas City, KS) and now at the Skaggs School of Pharmacy and Pharmaceutical Sciences of the University of Colorado (Aurora, CO) are tackling the intricacy of drug metabolism in neonates.

Sylvie

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Scientific contributions

Proposed schematic of hepatic CYP3A7 inhibition by ritonavir in neonates
Inhibition of CYP3A7 DHEA-S oxidation by LPV/r: an alternative mechanism for adrenal impairment in HIV antiretroviral-treated neonates

The ritonavir-boosted lopinavir regimen, known as Kaletra, has been associated with premature birth and transient adrenal insufficiency in newborns, accompanied by increases in plasma dehydroepiandrosterone 3-sulfate (DHEA-S). Our data suggest that ritonavir, a potent CYP3A7 time-dependent inhibitor, has a profound impact on metabolism of the endogenous androgenic hormone DHEA-S. Furthermore, the clearance rate of lopinavir in neonatal HLMs was much slower than in adult HLMs, suggesting that the addition of ritonavir in the cocktail therapy may not be necessary to maintain effective concentrations of lopinavir in neonates. These results may lead to a reconsideration of the use of ritonavir in neonatal antiretroviral therapy.

In silico docking of 2α-hydroxytestosterone in CYP3A7
Metabolism of drugs and steroids by CYP3A7 and implication for the neonatal liver functions

Study of the metabolic profile of the HIV non-nucleoside reverse transcriptase inhibitor nevirapine by CYP3A7 showed change in metabolite ratio compare to CYP3A4. This ratio difference may mean possible increase production of the hepatotoxic quinone methide metabolite and increased risks of toxicity for the neonates receiving this ART regimen. Furthermore, while investigating the metabolism of testosterone by CYP3A enzymes, our data supported an alternative binding mode for testosterone in CYP3A7 favoring the 2α-hydroxylation and therefore suggesting significant structural differences in its active site compared with CYP3A4/5.

Methyl jasmonate
Plant cytochrome P450 fatty acid hydroxylases

During my Ph.D., I carried out research to understand the role of a wheat cytochrome P450, CYP709C1, in plant defense and its potential implication in plant xenobiotic detoxification. I characterized a cytochrome P450 from Arabidopsis thaliana, CYP94C1, catalyzing dicarboxylic fatty acid formation in vitro, that was shown to be involved in the regulation of the jasmonate hormonal pathway important for the plant defense and developmental processes.

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Education

Postdoctorate
Pharmaceutical Chemistry

University of California
San Francisco, CA

2010

Ph.D.
Biochemistry and Molecular Biology

University of Strasbourg
Strasbourg, France

2006

M.S.
Biochemistry and Molecular/Cellular Biology

University of Strasbourg
Strasbourg, France

2003

B.S.
Biochemistry

University of Strasbourg
Strasbourg, France

2001

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Publications

Characterization of fluorescent probe substrates to develop an efficient high-throughput assay for neonatal hepatic CYP3A7 inhibition screening

Inhibition of CYP3A7 DHEA-S Oxidation by Lopinavir and Ritonavir: An Alternative Mechanism for Adrenal Impairment in HIV Antiretroviral-Treated Neonates

Active metabolites in drug development

4-Methylpyrazole protects against acetaminophen hepatotoxicity in mice and in primary human hepatocytes

Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis

Digging Deeper into CYP3A Testosterone Metabolism: Kinetic, Regioselectivity, and Stereoselectivity Differences between CYP3A4/5 and CYP3A7

Variability in Potency Among Commercial Preparations of Berberine

Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development

Analysis of cytochrome P450 CYP119 ligand-dependent conformational dynamics by two-dimensional NMR and X-ray crystallography

Role of protein-protein interactions in cytochrome P450-mediated drug metabolism and toxicity

Cytochromes P450 CYP94C1 and CYP94B3 catalyze two successive oxidation steps of plant hormone Jasmonoyl-isoleucine for catabolic turnover

Isocyanides inhibit human heme oxygenases at the verdoheme stage

Arabidopsis thaliana CYP77A4 is the first cytochrome P450 able to catalyze the epoxidation of free fatty acids in plants

Characterization of a methyl jasmonate and wounding-responsive cytochrome P450 of Arabidopsis thaliana catalyzing dicarboxylic fatty acid formation in vitro

Cytochrome P450-dependent fatty acid hydroxylases in plants

Cloning, functional expression, and characterization of CYP709C1, the first sub-terminal hydroxylase of long chain fatty acid in plants. Induction by chemicals and methyl jasmonate

Visible light-induced oxidation of unsaturated components of cutins: a significant process during the senescence of higher plants