Isoherranen Lab


One of the main areas of interest in our lab is vitamin A and retinoic acid homeostasis with special focus on the processes that mediate the synthesis of retinoic acid from vitamin A and the elimination of retinoic acid from target cells and from the body. We research the biochemistry and clinical significance of the enzymes in the Cytochrome P450 family 26. These include CYP26A1, CYP26B1 and CYP26C1 that are responsible for the clearance of retinoic acid from the body. Our research projects include basic studies on how these enzymes function, their structure-function and their specific expression patterns in human and animal tissues. We also investigate how these enzymes maintain specific tissue health and how alterations in their activity and expression may play a role in disease progression or toxic effects of environmental factors or xenobiotics. As more discoveries are made in the genetics of these enzymes we are actively involved in projects that aim to characterize how genetic variability in CYP26 activity may affect risks of disease development. In the area of retinoic acid synthesis we work on characterizing the alcohol and aldehyde dehydrogenase enzymes that are responsible for formation of retinoic acid in various tissues with special focus on their expression and activity in the testes, kidney, liver, lung and the pancereas.

Drug therapy during pregnancy is often associated with many concerns regarding fetal safety and maternal health. Yet, more often than not chronic or pregnancy induced diseases such as epilepsy, gestational diabetes, hypertension, infectious diseases and depression necessitate drug treatment during pregnancy. In fact, it is estimated that about 65% of pregnant women ingest at least one drug other then prenatal vitamin or mineral supplement while pregnant. As such better understanding of how pregnant women differ from nonpregnant women and men in how they respond to drugs and how their bodies handle drugs is critically important. In addition, for any drug that is consumed by the pregnant mother, the unborn fetus is also almost always also exposed to the drug. Yet, different drugs result in very different exposures to the fetus. At present there is considerable evidence that drug disposition and the kinetics of the sojourn of the drug in the body are altered during pregnancy in a gestational stage and drug dependent manner. Our research is focused on improving our understanding on how and by how much drug disposition is altered during pregnancy. We are working on characterizing the mechanisms that result altered expression and activity of drug metabolizing enzymes during pregnancy and on clinical studies of how drug disposition is affected by pregnancy. Our lab is also part of the “University of Washington Program on Pharmacokinetics of Drugs of Abuse During Pregnancy UWPKDAP” with emphasis on understanding how exposure to drugs used to treat addiction and to drugs of abuse is altered during pregnancy and to what magnitude the fetus is exposed to these drugs at different stages of pregnancy.

Potential drug-drug interactions are a major concern in patients undergoing polytherapy. Preclinical identification of potential inhibitors and inducers of drug metabolizing enzymes and transporters is critically important in new drug development. In addition, since it is not possible to study every combination of potentially interacting drugs in the clinic, development of novel simulation and prediction methods for drug-drug and drug-disease interactions that allow extrapolation of clinical findings from one drug to another is critically important. We have several active research projects ongoing in the area of prediction, simulation and rationalization of complex drug-drug interactions. Such complex drug-drug interactions include drug-drug interactions that involve inhibitory metabolites, drug-drug interactions that are a result of inhibition of multiple enzymes and/or transporters, drug-drug interactions that are complicated by genetic variability and interactions in which coexisting diseases such as renal or hepatic impairment affect the magnitude of the observed interaction. Our work is focused on improving our understanding of the clinical importance of metabolites in precipitating drug-drug interactions and in developing better methods for preclinical risk assessment of potential inhibitors or inducers of drug metabolizing enzymes and drug transporters. We are also actively working on developing new simulation and modeling methods for complex drug-drug interactions