Cross Talk in Metabolism of Xenobiotics and Endogenous Substrates

Wednesday April 28, 2021

1:30 pm - 3:00 pm Eastern Time (ET)

View session on the EB Virtual Platform (EB registration required)

BEH DDD DMDD TOX

Chair :

Amit Pandey
University of Bern

Xinxin Ding
University of Arizona



While much is known about reactions and substrates of xenobiotic metabolizing enzymes, their specificity towards xenobiotics, drugs and endogenous substrates such as steroid hormones is less well understood. Protein-protein interactions also influence the substrate recognition and metabolism. The topics will address whether drug and steroid metabolizing enzymes can recognize different classes of substrates, how the substrate selection and activities are influenced and whether ambiguity in substrate recognition leads to unexpected metabolic activities.

Speakers

Rita Bernhardt - University of Saarland

Role of Steroid Hydroxylases in Drug and Xenobiotic Metabolism

Steroid hydroxylation by cytochromes P450 in the adrenals was thought for a long time to be highly specific and selective. We have demonstrated that mitochondrial P450s were able to convert the anabolic steroid turinabol. Moreover, spironolactone and its metabolite canrenone were shown to be converted in vitro by adrenal P450s as well as human adrenals.

Aditi Das - University of Illinois

Cross-talk of Cannabinoid and Endocannabinoid Metabolism is Mediated via Human Cardiac CYP2J2

Talk description coming soon!

D. Fernando Estrada - University at Buffalo

(Structural) Cross Talk in Vitamin-D Metabolism

Talk description coming soon!

Wen Xie - University of Pittsburgh

Sex and Tissue-Specific Roles of Estrogen Sulfotransferase and Steroid Sulfatase

Sulfonation and de-sulfonation are essential to maintain the chemical and functional homeostasis of numerous xenobiotic and endobiotics. This presentation will focus on the sex and tissue-specific roles of estrogen fulfotransferase and steroid sulfatase in diseases.

Yifan Bao - University of Connecticut

An Injured liver caused by Overdose of Acetaminophen has Altered Expression and Activities of P450 Enzymes and Associated Drug Efficacy During Liver Recovery and Regeneration

Acetaminophen (APAP)-induced liver injury (AILI) is the leading cause of acute liver failure in the United States. Alterations on therapeutic efficacy and adverse drug reactions (ADRs) in patients with AILI are not fully investigated. Our previous study showed that AILI could result in dose-dependent and immediate decreases in expression and activities of major hepatic drug-metabolizing cytochrome P450s (P450s) enzymes in mice. However, liver will go through regeneration after AILI. How P450-mediated drug metabolism alters during liver regeneration is unclear. The aim of the study was to investigate the alterations in expression and activities of major P450 enzymes and associated drug efficacy and ADRs during liver regeneration after AILI. Adult male C57BL6/J mice were treated with various doses of APAP at 0 (no damage control), 200 (mild damage and recoverable), 400 (severe damage but recoverable), and 600 mg/kg (life-threatening damage and unrecoverable). The mice were sacrificed at 24, 48, 72, and 96 hours after the APAP treatment. Severity of liver damage was detected by plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and miR122, with further confirmation by H & E staining in liver tissue sections. The expression and activities of CYP1A2, 2B10, 2C29, 2E1, and 3A11 were measured by RT-PCR (mRNAs) and MS/MS quantification of probe drugs, respectively. Sedation efficacy of midazolam was monitored at different time points after APAP treatment at different doses. The levels of ALT and AST significantly increased at 24 hours after APAP treatment at 200 and 400 mg/kg but dropped back to normal levels at 72 and 96 hours. No mice treated with 600 mg/kg APAP could survive to 72 hours. The magnitude of liver damage was further confirmed by H & E staining. The major examined P450 enzymes showed significant decreases at 24 hours in gene expression and activity levels and recovered back to normal with the doses of 200 and 400, but not 600 mg/kg of APAP. The activities of examined major P450s are correlated with the levels of ALT, AST, and mir122. The alterations of CYP3A11 resulted in correlated changes in sedation efficacy as reflected by sleeping times with midazolam treatment. These results indicated that P450 expression and function could recover after mild and even severe, but not lethal AILI. Overall, these results suggest that ALT, AST, and miR122 are potential biomarkers for predicting how alterations in P450 activities can justify dose selection of other drugs for desired efficacy. Further studies are needed to confirm these findings in human patient populations with AILI and to understand the underlying molecular mechanisms mediating recovery of hepatic P450s during AILI.

Last Updated: February 8, 2021
Key Dates
 
April 27 – 30, 2021

ASPET Annual Meeting at EB 2021

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