Laboratory of Pharmaceutical Health Science

Pharmaceutical health science is one of the most important research fields in the School of Pharmaceutical Sciences. It contributes to the prevention of diseases by investigating the causes of various diseases and assessing the health effects of exposure to chemicals and the associated mechanisms. In our laboratory, three faculty members, Professor Shigeru Ohta, Associate Professor Seigo Sanoh, and Assistant Professor Naoki Takaoka are conducting research studies on chemicals.
Chemicals include pharmaceuticals, food additives, cosmetics, fragrances, detergents, and pesticides. These chemicals are indispensable in our daily lives, and the number of chemicals that are registered each year is increasing exponentially. However, the toxicity and safety of many of these chemicals after exposure are still not fully understood.
As the immune system protects the body from viral or bacterial infection, the body has a detoxification mechanism to eliminate chemicals after exposure. This occurs through a process known as drug (xenobiotic) metabolism. It is a physiological function that is very important when considering the toxicity and safety of chemicals. For example, when oral exposure to chemicals occurs, the chemicals are absorbed through the gastrointestinal tract into the systemic circulation, where they are distributed to various tissues, metabolized by drug (xenobiotic)- metabolizing enzymes that are expressed mainly in the liver, and excreted in urine and feces as detoxified metabolites.
However, some chemicals are not detoxified by drug-metabolizing enzymes in the liver but produce toxic metabolites (active metabolites or reactive metabolites). This is an unintended reaction for the organism, and it is very difficult for researchers to make predictions on this. It is known that the formation of such toxic metabolites is also involved in the side effects of pharmaceuticals, causing toxic effects on various organs, such as the liver and brain.
Therefore, we have performed in vivo studies using mice and rats, in vitro studies using cells and tissues, and in silico studies using computers (simulations) to predict toxicity in humans through drug metabolism, which is called risk assessment. We aim to identify the determinants of toxicity and elucidate their mechanisms as well as establish a system for predicting the toxicity of chemicals in humans, considering drug metabolism and disposition (formation of metabolites and pharmacokinetics), through joint research with domestic or overseas research institutions. We hope to contribute to the accurate risk assessment of chemicals and the development of safer drugs.

Member

■Professor, Shigeru OHTA (Ph.D.)　 　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　■Associate Professor, Seigo SANOH (Ph.D.)　　　　　　　　　　　　　　　　　　　　　　　　　　　　　■Assistant Professor, Naoki TAKAOKA (Ph.D.)

Research

(1)Prediction of pharmacokinetics and toxicity of chemicals, such as pharmaceuticals, in humans
　One of the factors that make the risk assessment of chemicals difficult is the specie differences in animals and humans as well as variances between in vitro and in vivo profiles. Therefore, a system that can facilitate in vivo assessment in humans is required. We used chimeric mice with humanized livers, in which the mouse liver was replaced by human hepatocytes, to predict the disposition of chemicals metabolized in the human liver. Since various human drug-metabolizing enzymes are expressed in chimeric mice with humanized livers, the mice are expected to serve as a system for evaluating the metabolism and disposition of chemicals in humans. In addition, we evaluated the prediction of drug- induced hepatotoxicity (cholestasis and steatosis) using chimeric mice with humanized livers. In this study, we aimed to explore the key molecules involved in the onset of hepatotoxicity and elucidate the detailed mechanism, which will lead to the development of biomarkers that can monitor the onset of hepatotoxicity.

(2) Elucidation of a novel regulatory mechanism associated with the expression of drug-metabolizing enzymes
　We are investigating the regulatory mechanism of expression from transcription to translation and proteolysis of drug-metabolizing enzymes (cytochrome P450 and aldehyde oxidase) that are abundantly expressed in the liver. The expression of drug-metabolizing enzymes is known to be altered in response to internal and external environmental changes in vivo (e.g. chemical exposure and pathological conditions).
This finding may be a contributing factor to the individual differences in drug metabolism and toxicity. In particular, we are studying the regulatory mechanism of the expression of drug-metabolizing enzymes by inter-organ communication between the liver and extra-hepatic tissues (e.g. the intestinal tract).

(3) Elucidation of the novel physiological functions of drug-metabolizing enzymes and their relationship with diseases
　Some drug-metabolizing enzymes are expressed in extra-hepatic organs and are known to be responsible for physiological functions other than the metabolism of endogenous chemicals, such as vitamins and arachidonic acid. However, its physiological significance is not yet fully understood. If the metabolic mechanism is altered, this may lead to diseases. In particular, we are focusing on the physiological functions of cytochrome P450 and aldehyde oxidase as well as their involvement in diseases.