Remember me
The special section of “Cytochrome P450 enzymes in toxicology and as drug targets” in the June 2024 issue of Drug Metabolism and Disposition (DMD) is contributed by Dr. Klarissa D. Jackson, the recipient of the 2023 Richard Okita Early Career Award in Drug Metabolism and Disposition (Okita Award, Fig. 1), and her mentors, trainees, and colleagues.
Fig. 1. Dr. Klarissa D. Jackson was the recipient of the Richard Okita Early Career Award in Drug Metabolism and Disposition, awarded by the Division for Drug Metabolism and Disposition (DMDD) of the American Society for Pharmacology and Experimental Therapeutics (ASPET) in 2023. Photos are reproduced with permission from Dr. Jackson.
Dr. Klarissa D. Jackson earned her Ph.D. degree in pharmacology from Vanderbilt University School of Medicine in the laboratory of Dr. Jason Morrow and Dr. L. Jackson Roberts. Her dissertation research investigated the formation and metabolism of chemically reactive cyclopentenone prostaglandins and isoprostanes under settings of oxidative stress. Dr. Jackson completed her postdoctoral training in the Department of Medicinal Chemistry at the University of Washington School of Pharmacy under the mentorship of Dr. Allan Rettie and Dr. Sidney Nelson. As a postdoctoral fellow, she studied the role of cytochrome P450 (P450)-mediated metabolic activation in the mechanisms of hepatotoxicity associated with the tyrosine kinase inhibitor lapatinib.
Dr. Jackson began her faculty career in July 2013 as an Assistant Professor in the Department of Pharmaceutical Sciences at Lipscomb University College of Pharmacy. In July 2019, she was recruited to the University of North Carolina (UNC) at Chapel Hill Eshelman School of Pharmacy as an Assistant Professor in the Division of Pharmacotherapy and Experimental Therapeutics. Dr. Jackson’s research laboratory focuses on understanding the mechanisms of interindividual variability in drug metabolism in ethnically diverse populations and the impact on drug efficacy and toxicity. Her mechanistic and translational work emphasizes the importance of including understudied ancestry populations in drug metabolism research to optimize drug therapy and advance precision medicine for all patients.
Dr. Jackson’s research has made significant contributions to defining the roles of P450 enzymes in the metabolic activation of tyrosine kinase inhibitors associated with hepatotoxicity. Studies from her laboratory indicate that genetic and environmental factors contribute to interindividual variability in tyrosine kinase inhibitor metabolism and bioactivation, which may influence individual exposure to reactive, potentially toxic metabolites. More recently, her team has published work on the role of P450 and non-P450 enzymes in the metabolism of cannabidiol, which is associated with dose-dependent hepatotoxicity in the treatment of seizures associated with severe epilepsy syndromes. Given the growing medical and consumer interest in cannabidiol, this research is critical to ensure patient and consumer safety.
Dr. Jackson has received numerous scientific awards and recognitions, including the Pharmaceutical Sciences Impact Award from Lipscomb University College of Pharmacy, the Early Career Award from the American Society for Pharmacology and Experimental Therapeutics (ASPET) Division for Translational and Clinical Pharmacology, and the Translational Science Research Award from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Network of Minority Health Research Investigators. Dr. Jackson’s research has been supported by an NIH National Institute of General Medical Sciences (NIGMS) Maximizing Investigators’ Research Award (MIRA) for Early-Stage Investigators and previously by an NIH National Cancer Institute (NCI) K01 Research Scientist Development Award. Dr. Jackson has actively served in leadership positions in the ASPET Division for Drug Metabolism and Disposition, and she is a member of the Editorial Board of Drug Metabolism and Disposition.
Dr. Jackson and coauthors provide a central theme minireview of “Kinase inhibitors FDA-approved 2018–2023: drug targets, metabolic pathways, and drug-induced toxicities” (Latham et al., 2024), highlighting important aspects of the clinical pharmacology and toxicology of 42 small-molecule kinase inhibitors (KIs) approved by the US Food and Drug Administration (FDA) during 2018–2023 for cancer and other indications. The article describes key advances in the therapeutic indications, molecular targets, major metabolism pathways, and toxicity profiles of the 42 KIs. Clinically relevant case examples are also provided to emphasize the risk for hepatotoxic drug interactions involving tyrosine kinase inhibitors (TKIs) and coadministered drugs. The minireview concludes with a discussion of perspectives on future research to optimize TKI therapy to maximize efficacy and minimize drug toxicity.
Dr. F. Peter Guengerich, Professor of Biochemistry at Vanderbilt University School of Medicine, served as Dr. Jackson’s faculty mentor for her NIH NCI K01 Research Scientist Development Award (2014–2019) while she was on faculty at Lipscomb University in Nashville, Tennessee. Dr. Guengerich provided valuable mentorship on studies related to cytochrome P450 enzymology. In this special section, Dr. F. Peter Guengerich contributes a minireview on “Cytochrome P450 enzymes as drug targets in human disease” (Guengerich, 2024). The article summarizes major physiologic functions of human cytochrome P450 (P450) enzymes, including members of CYP5A1, 11A1, 11B1, 11B2, 17A1, 19A1, and 51A1, and their implications in certain human diseases such as cancer. By selectively inhibiting the certain P450 enzymes (e.g., CYP19A1), multiple steroid aromatase inhibitor drugs, including exemestane, letrozole, anastrozole, have been developed in the treatment of breast cancer. The article also discusses other P450 enzymes such as CYP2A6, 8B1, 4A11, 24A1, 26A1, and 26B1 as drug targets that are less developed. The selective inhibition of certain P450 enzymes having major physiologic functions has been shown to be very efficacious in the development of therapeutic agents for the treatment of certain human diseases.
Dr. Allan Rettie, Professor of Medicinal Chemistry at the University of Washington School of Pharmacy, was Dr. Jackson’s mentor during her postdoctoral fellowship at the University of Washington (2011–2013). Dr. Rettie graciously served as her postdoctoral mentor after the passing of her mentor Dr. Sidney Nelson in 2011. In this special section, Dr. John Kowalski and Dr. Allan Rettie contribute a minireview article on “There and back again: a perspective on 20 years of CYP4Z1” (Kowalski and Rettie, 2024). CYP4Z1 is the last P450 enzyme to be identified in the human genome and is involved in bioactivation of lipid metabolites, influencing tumor growth and metastasis. Its functions make CYP4Z1 an attractive target for new chemotherapeutic drug development. This review summarizes the current state of knowledge regarding the biochemistry of CYP4Z1, its role in breast cancer, and the recent synthesis of selective chemical inhibitors of the enzyme.
Dr. Jessica Beers was a Ph.D. graduate student in Dr. Jackson’s laboratory at the UNC Eshelman School of Pharmacy (2019–2023). As a part of her dissertation project, Dr. Beers studied the metabolism, pharmacokinetics, and hepatotoxicity of cannabidiol. Prior to starting at UNC, Dr. Beers was a Pharm.D. research student in Dr. Jackson’s laboratory at Lipscomb University College of Pharmacy (2015–2018). Dr. Beers is now a postdoctoral fellow in the Department of Pharmaceutics at the University of Washington School of Pharmacy. In this special section, Dr. Jessica Beers and coauthors contribute a minireview on “Advances and challenges in modeling cannabidiol pharmacokinetics and hepatotoxicity” (Beers et al., 2024). Cannabidiol (CBD) is a natural product approved by the FDA as an antiepileptic drug and is known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. This review describes current modeling approaches to capture the pharmacokinetics and metabolic clearance of CBD. CBD-induced liver injury is summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.
Dr. Jed Lampe, Associate Professor at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, is Dr. Jackson’s colleague in the drug metabolism field. Dr. Lampe has a shared interest in studying CYP3A enzymology in understudied populations. In this special section, Dr. Jed N. Lampe and coauthors publish a research article on “HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation” (Work et al., 2024). The prevalence of hepatitis C virus (HCV) in pregnant people is estimated to be between 1% and 8% of the global population, and many of these mothers may receive antiviral drugs. Fetal hepatic CYP3A7 is the primary P450 enzyme expressed in fetal liver for estriol production. Little to no information exists about the risk that antiviral treatment poses to the developing fetus. A potential risk may exist that affects mother-fetal communication through the inhibition of fetal hepatic CYP3A7 by the antiviral drugs. This study discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, demonstrating the potential threat that these drugs pose to proper fetal development.
The articles in this special section collectively address the importance of physiologic functions of certain P450 enzymes and their implications in the development of human diseases. Targeting these P450 enzymes can serve as an approach to develop therapeutic intervention for the treatment of human diseases. Metabolites produced by the P450 enzymes may also underlie the mechanisms for drug-induced toxicity.
Authorship ContributionsWrote or contributed to the writing of the manuscript: Zhong, Lai.
FootnotesThis work received no external funding.
The authors declare that they have no conflicts of interest with the contents of this article.
AbbreviationsASPETAmerican Society for Pharmacology and Experimental TherapeuticsCBDcannabidiolFDAUS Food and Drug AdministrationHCVhepatitis C virusNIHNational Institutes of HealthP450cytochrome P450UNCUniversity of North CarolinaCopyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics
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