C3H mouse embryo fibroblast cells, designated 10T1/2, can be transformed by physical and chemical agents including polycyclic aromatic hydrocarbons. In a previous report (Shen et al., Proc. Natl. Acad. Sci. USA 90, 11483-11487, 1993), we identified a cytochrome P450 gene induced by polycyclic aromatic hydrocarbons (PAHs) that is different from 1A1 or 1A2, and which we tentatively named P450CMEF. Here, we report the entire cDNA sequence of P450CMEF (5,128 bp) and the amino acid sequence deduced from it (543 residues). A comparison of the latter sequence with known cytochrome P450s indicates that P450CMEF is in a new subfamily of family 1 of the P450 superfamily. Accordingly, the Committee on Standardized Cytochrome P450 Nomenclature designated the gene Cyp1b1. Exposure to various aryl hydrocarbons (2.5 hr) induced Cyp1b1 mRNA in 10T1/2 cells to different degrees: 2,3,7,8-tetrachlorodibenzo-p-dioxin, 7,12-dimethylbenz[a]anthracene, benz[a]anthracene, benzo[a]pyrene, and beta-naphthoflavone were strong inducers; alpha-naphthoflavone and 3-methylcholanthrene, were moderate inducers; and benzo[e]pyrene was a weak inducer.
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http://dx.doi.org/10.1089/dna.1994.13.763 | DOI Listing |
J Headache Pain
January 2025
Department of Neurology, Koventhospital Barmherzige Brüder, Linz, Austria.
Background: Proton pump inhibitor (PPI) drugs are widely used and are among the most significant achievements of modern pharmacology. Their primary purpose is treating and preventing gastric acid-related disorders. Migraine and PPI intake are prevalent, and many people are affected by both.
View Article and Find Full Text PDFDrug Metab Dispos
January 2025
Department of Pharmacotherapy and Translational Research, College of Pharmacy, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida. Electronic address:
Many factors cause interperson variability in the activity and expression of the cytochrome P450 (CYP) drug-metabolizing enzymes in the liver, leading to variable drug exposure and treatment outcomes. Several liver-enriched transcription factors are associated with CYP expression, with estrogen receptor α (ESR1) and constitutive androstane receptor (CAR or NR1I3) being the 2 top factors. ESR1 and NR1I3 undergo extensive alternative splicing that results in numerous splice isoforms, but how these splice isoforms associate with CYP expression is unknown.
View Article and Find Full Text PDFDrug Metab Dispos
January 2025
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan; WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Pirfenidone (PIR) is used in the treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver.
View Article and Find Full Text PDFDrug Metab Dispos
January 2025
Current affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Current affiliation: OneDrug Inc., Toronto, Ontario, Canada; Program in Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom. Electronic address:
Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized patients with COVID-19. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary cytochrome P450 (CYP) 3A4 affects drug concentrations, especially in the lung tissue, which is most affected by the disease. Herein, physiologically based pharmacokinetic modeling was used to demonstrate the differences in systemic and pulmonary concentrations of 4 respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19-CYP3A4 interactions at varying severity levels including outpatients, non-intensive care unit (ICU), and ICU patients.
View Article and Find Full Text PDFDrug Metab Dispos
January 2025
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Predictions of drug-drug interactions resulting from time-dependent inhibition (TDI) of CYP3A4 have consistently overestimated or mispredicted (ie, false positives) the interaction that is observed in vivo. Recent findings demonstrated that the presence of the allosteric modulator progesterone (PGS) in the in vitro assay could alter the in vitro kinetics of CYP3A4 TDI with inhibitors that interact with the heme moiety, such as metabolic-intermediate complex forming inhibitors. The impact of the presence of 100 μM PGS on the TDI of molecules in the class of macrolides typically associated with metabolic-intermediate complex formation was investigated.
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