Description
Background
Protein malnutrition remains a major global health problem and frequently co-occurs with alcohol use, opioid exposure, and infectious disease, particularly in low- and middle-income settings. The liver is central to both metabolism and inflammatory regulation, yet the effects of a malnutrition-like nutrient environment on hepatic responses to combined metabolic and inflammatory insults are not well defined. Cytochrome P450 3A4 (CYP3A4), a key enzyme involved in opioid metabolism, is highly sensitive to inflammatory signaling and may be especially vulnerable under conditions of nutritional deficiency. This project aims to 1) develop an in vitro model of nutritionally competent versus amino acid–restricted primary human hepatocytes (PHHs) and 2) examine how nutritional status modulates hepatic responses to ethanol, opioids, and bacterial inflammatory stimuli. A secondary objective is to evaluate the ability of pharmacologic interventions (naloxone, naltrexone, and antibiotic therapy) to restore hepatic function following injury.
Methods
PHHs will be cultured under control or partial essential amino acid–restricted conditions to model protein malnutrition. Optional co-culture with human macrophages will be used to incorporate inflammatory crosstalk. Hepatocytes will be exposed to continuous ethanol and morphine, followed by bacterial inflammatory stimulation using Escherichia coli. Opioid antagonists will be administered after injury to model rescue. The primary endpoint will be recovery of CYP3A4 activity at 48- and 72-hours post-intervention. Secondary outcomes will include cytotoxicity, hepatocyte synthetic and metabolic function, and inflammatory cytokine production.
Expected Outcomes
This study is expected to define how protein malnutrition alters hepatic susceptibility to metabolic and inflammatory stress and modulates recovery of drug-metabolizing capacity. The findings will provide insight into the clinical importance of nutritional status in drug metabolism and inflammatory response, with implications for substance use and infection management in malnourished populations.
Conclusion
Protein malnutrition enhances hepatic vulnerability to metabolic and inflammatory stress and impairs recovery of drug-metabolizing capacity. By modeling nutrient-inflammatory interactions that influence CYP3A4 function, this work highlights broader principles of hepatic stress adaptation and recovery that extend beyond malnourished populations, with implications for medication safety, substance use, and infection-associated inflammation across diverse clinical settings.
Disciplines
Biochemical Phenomena, Metabolism, and Nutrition | Biological Phenomena, Cell Phenomena, and Immunity | Chemical and Pharmacologic Phenomena | Medical Immunology | Medical Microbiology | Medical Pharmacology
Document Type
Poster
Recommended Citation
Kantety, Vijitha D. and Jiminez, Victor Jr., "When Nutrition Fails: Modeling Protein Malnutrition-Driven Vulnerability in Hepatic Drug Metabolism and Inflammatory Stress" (2026). Annual Research Symposium. 5.
https://ecommons.roseman.edu/researchsymposium/2026/basic_sciences/5
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Chemical and Pharmacologic Phenomena Commons, Medical Immunology Commons, Medical Microbiology Commons, Medical Pharmacology Commons
When Nutrition Fails: Modeling Protein Malnutrition-Driven Vulnerability in Hepatic Drug Metabolism and Inflammatory Stress
Background
Protein malnutrition remains a major global health problem and frequently co-occurs with alcohol use, opioid exposure, and infectious disease, particularly in low- and middle-income settings. The liver is central to both metabolism and inflammatory regulation, yet the effects of a malnutrition-like nutrient environment on hepatic responses to combined metabolic and inflammatory insults are not well defined. Cytochrome P450 3A4 (CYP3A4), a key enzyme involved in opioid metabolism, is highly sensitive to inflammatory signaling and may be especially vulnerable under conditions of nutritional deficiency. This project aims to 1) develop an in vitro model of nutritionally competent versus amino acid–restricted primary human hepatocytes (PHHs) and 2) examine how nutritional status modulates hepatic responses to ethanol, opioids, and bacterial inflammatory stimuli. A secondary objective is to evaluate the ability of pharmacologic interventions (naloxone, naltrexone, and antibiotic therapy) to restore hepatic function following injury.
Methods
PHHs will be cultured under control or partial essential amino acid–restricted conditions to model protein malnutrition. Optional co-culture with human macrophages will be used to incorporate inflammatory crosstalk. Hepatocytes will be exposed to continuous ethanol and morphine, followed by bacterial inflammatory stimulation using Escherichia coli. Opioid antagonists will be administered after injury to model rescue. The primary endpoint will be recovery of CYP3A4 activity at 48- and 72-hours post-intervention. Secondary outcomes will include cytotoxicity, hepatocyte synthetic and metabolic function, and inflammatory cytokine production.
Expected Outcomes
This study is expected to define how protein malnutrition alters hepatic susceptibility to metabolic and inflammatory stress and modulates recovery of drug-metabolizing capacity. The findings will provide insight into the clinical importance of nutritional status in drug metabolism and inflammatory response, with implications for substance use and infection management in malnourished populations.
Conclusion
Protein malnutrition enhances hepatic vulnerability to metabolic and inflammatory stress and impairs recovery of drug-metabolizing capacity. By modeling nutrient-inflammatory interactions that influence CYP3A4 function, this work highlights broader principles of hepatic stress adaptation and recovery that extend beyond malnourished populations, with implications for medication safety, substance use, and infection-associated inflammation across diverse clinical settings.