Extrahepatic Drug‐Metabolizing Enzymes and Their Significance

Abstract

Drug‐metabolizing enzymes (DMEs) are primarily expressed in the liver but their role in the extrahepatic tissues such as gastrointestinal tract (GIT), pulmonary, excretory, nervous, cardiovascular system, and skin cannot be neglected. Generally, the expression of DMEs in extrahepatic tissues is quantitatively lower than that in the liver, but there are a few enzymes such as CYP1A1, CYP1B1, CYP2F1, and CYP2U1 that are more abundant in extrahepatic organs. As many extrahepatic organs are portals for administered drugs, DMEs expressed in these organs can be responsible for significant metabolism, leading to first‐pass effects and lower bioavailability. Extrahepatic DMEs are also involved in bioactivation of prodrugs and formation of reactive metabolites that may interact with cellular components, resulting in organ‐specific toxicity. Activity and expression of extrahepatic DMEs is often altered by coadministered drugs, leading to drug–drug interactions. Expression of DMEs in living beings affected by a host of environmental and genetic factors such as genetic polymorphism, age, gender, pathophysiological conditions, inborn errors in metabolism, food habits, and environmental pollutants, contributing to varied drug effects and idiosyncratic toxicities.

Metabolite identification studies on amiodarone in in vitro (rat liver microsomes, rat and human liver S9 fractions) and in vivo (rat feces, urine, plasma) matrices by using liquid chromatography with high‐resolution mass spectrometry and multiple‐stage mass spectrometry: Characterization of the diquinone metabolite supposedly responsible for the drug's hepatotoxicity

“…The targeted ortho ‐diquinone metabolite was formed in all likelihood through the dihydrodiol intermediate, which was also observed in this study as metabolite M4. It is hypothesized that M4 itself was formed through an epoxide intermediate, which incidentally was not observed in our study, perhaps due to its rapid conversion into M4 or its highly reactive nature, which is a well‐known phenomenon for epoxides . The epoxide intermediate is thus shown in a dotted box in Fig.…”

Targeted label-free approach for quantification of epoxide hydrolase and glutathione transferases in microsomes

“…Known levels of CYP450 enzymes in human liver microsomes.The expressed metabolism enzymes in extrahepatic organs could 257 be responsible for drug metabolism, leading to a first-pass effect, 258 lower bioavailability, and drug-inactivated and drug-drug interac-259 tions[30]. In the present study, the expressions of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 in lung, kidney, and intestine are…”

“…a b s t r a c t 28 The aim of this study was to investigate the expression and organ distribution of cytochrome P450 29 (CYP450) enzymes, microsomal epoxide hydrolase (MEH), and microsomal glutathione-S-transferase 30 (MGST 1, 2, 3) in human liver, lung, intestinal, and kidney microsomes by targeted peptide-based quan- 31 tification using nano liquid chromatography-tandem multiple reaction monitoring (nano LC-MRM). 32 Applying this method, we analyzed 16 human liver microsomes and pooled lung, kidney, and intestine 33 microsomes.…”

Do We Need to Study Metabolism and Distribution in the Eye: Why, When, and Are We There Yet?

“…It is well understood that the liver plays a major role in the biotransformation of drug molecules; quantitatively, it expresses the highest total level of DMEs. However, all tissues express DMEs to some extent, 58 and in some cases, they may express a specific isoform at a greater level than in the liver, or one that may be absent in the liver (e.g., UGT2A1 in lungs). 59 Analogous to hepatic DMEs, the expression of DMEs in extrahepatic tissues is affected by a variety of genetic and environmental factors.…”