- CYP 2D6 is also known as debrisoquine hydroxylase, which catalyzes the oxidation of approximately a quarter of all the commonly used therapeutic drugs in clinical practice today. For instance, Codeine is metabolized by CYP2D6 to morphine. In such cases, enhanced CYP2D6 activity (i.e., in CYP2D6 ultra-rapid metabolizers) predisposes one to opioid intoxication.
- CYP 2C19 (S-mephenytoin hydroxylase) acts on weakly or strongly basic drugs containing one hydrogen bond donor, or if there are functional groups containing carbon or sulfur, double bonded to oxygen present in the substrate. CYP 2C19 is responsible for the metabolism of anticonvulsant drugs, proton pump inhibitors, and drugs that inhibit platelet function.
- CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. It is the most abundantly expressed P450 in human liver and it is known to metabolize more than 120 different drugs. Examples of CYP3A4 Substrates relevant in human space flight include: acetaminophen, diazepam, erythromycin, lidocaine, lovastatin, and warfarin. CYP3A4 also is sensitive to enzyme induction, which tends to lower plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of the substrate.
1) SNP Variant Profiles of Phase II Conjugation Enzymes. For instance, UGT (UDP glucuronosyltransferases) is an enzymatic superfamily, which is involved in conjugation of endogenous compounds (bilirubin, steroidal hormones, thyroid hormones, biliary acids, vitamins) and exogenous compounds (drugs, carcinogens, and polluting dietary elements) that are transformed in N-, O-, S-, C- glucuronates. They are responsible for roughly 35% of Phase II reactions. Understanding genetic variants of Phase II enzymes will be helpful in designing individualized drug regimens.
2) Adequacy of Nutrient Cofactors of Phase II Enzymes (e.g. riboflavin as cofactor for glutathione-S-transferase and glutathione reductase): Assess pre-flight status of all nutrient cofactors of drug biotransformation, using serum, plasma, or cells (RBC, WBC) to ensure optimum status for each individual astronaut. If warranted by genotype, provide nutrient cofactor at dosage commensurate with the allelic variant (e.g. wild type, heterozygote, homozygote).
3) Conjugation Agents that Directly Bind Drugs, as Part of Phase II Conjugation: Assess pre-flight status of key conjugation agents (e.g. glutathione, glycine, cysteine, glutamine, arginine, taurine, acetate) to ensure optimum status for that individual. This can be done by plasma amino acid profiles or, in the case of glutathione, white blood cells or whole blood.
Our services in support of pharmacogenomics and pharmacometabolomics in spaceflight span four primary areas. These include:
- Research: Our research collaborations support investigator teams working to study the application of pharmacogenomics and pharmacometabolomics in spaceflight research.
- Countermeasure Strategy: This is closely aligned with research, and involves development of strategies and specifications that can be deployed into the spaceflight environment
- Clinical: Our clinical support can assist spaceflight medical directors, flight providers, spaceflight participants, and other associated with spaceflight to profile and assess individual and team pharmacogenomic profiles, as part of countermeasure development with the goal of optimizing mission safety.
- Training: We work with our clients/collaborators on two primary areas of training relative to spaceflight pharmacogenomics:
- General training in the subject matter, which includes theory, current applications, and limitations
- Training associated with our Spaceflight First Responder and Spaceflight Advanced Life Support programs. These incorporate concepts of pharmacogenomics, as pre-mission logistical considerations aimed at optimizing the space flight experience and limiting adverse events.
For more information, look for our forthcoming book chapter (Springer, 2018) Pharmacogenomics & Pharmacometabolomics in Spaceflight
Schmidt, MA, Goodwin, Thomas TJ, Lloyd, C, Kaddurah-Daouk, R. (2018) Pharmacogenomics and Pharmacometabolomics in Spaceflight: One Pillar of Personalized Precision Medicine, In: Handbook of Space Pharmaceuticals [Pathak, Y, dos Santos, M, & Zea, L, Eds.© 2018]