Cell systems

 Cytochrome P450 (CYP) 

The cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins that play a pivotal role in the detoxification of xenobiotics, cellular metabolism and homeostasis. Induction or inhibition of CYP enzymes is a major mechanism that underlies drug-drug interactions. CYP enzymes can be transcriptionally activated by various xenobiotics and endogenous substrates through receptor-dependent mechanisms. CYP enzyme inhibition is a principal mechanism for metabolism- based drug-drug interactions. Many chemotherapeutic drugs can cause drug interactions due to their ability to either inhibit or induce the CYP enzyme system. Predictions based on in silico analyses followed by validation have identified several microRNAs that regulate CYPs. Genetic polymorphisms and epigenetic changes in CYP genes may be responsible for inter-individual and interethnic variations in disease susceptibility and the therapeutic efficacy of drugs. 

Knowledge about the substrates, inducers, and inhibitors of CYP isoforms, as well as the polymorphisms of CYP enzymes may be used as an aid by clinicians to determine therapeutic strategy, and treatment doses for drugs that are metabolized by CYP gene products. 

 UDP-glucuronosyltransferases 

Human UDP-glucuronosyltransferase (UGT) exists as a superfamily of 22 proteins, which are divided into 5 families and 6 subfamilies on the basis of sequence identity. Members of the UGT1A and 2B subfamilies play a key role in terminating the biological actions and enhancing the renal elimination of non-polar (lipophilic) drugs from all therapeutic classes. These enzymes primarily catalyse the covalent linkage of glucuronic acid, derived from the cofactor UDP-glucuronic acid, to a substrate with a suitable acceptor functional group. This process is referred to as glucuronidation. While the liver is the major detoxification organ, and as such contains the greatest abundance and diversity of UGTs, these enzymes also exhibit significant, but variable extra-hepatic expression. 

Functionalisation and conjugation reactions involved in drug metabolism are enzymatically mediated. Quantitatively, the most important functionalisation and conjugation enzymes are the cytochromes P450 (CYP) and UDP-glucurosyltransferase (UGT), respectively. These enzymes are responsible for the clearance of more than 90% of drugs that are dependent on hepatic clearance (CLH) for elimination from the body. In the majority of cases, drug metabolism serves as a detoxification mechanism as the metabolites formed are less biologically active than the parent compound. However, in some cases the drug is converted to a highly reactive metabolite that has increased pharmacological activity or is toxicologically active. For example, the analgesic drug codeine is metabolised by CYP2D6 to form the active metabolite morphine, which elicits analgesia (Caraco et al., 1999). Further metabolism of morphine by the enzyme UGT2B7 results in the formation of morphine-6-glucuronide, which is a 100-times more potent μ-opioid receptor agonist than morphine itself (Paul et al., 1989). 

Tissue localisation

It is well established that the liver has the greatest abundance and array of UGT  enzymes (Izukawa et al., 2009, Ohno and Nakajin, 2009, Court et al., 2012). In addition to hepatic expression, UGT1A and UGT2B enzymes are also differentially expressed in a range of other tissues including the kidneys, small intestine, colon, stomach, lungs, epithelium, ovaries, testis, mammary glands and prostate (Tukey and Strassburg, 2000, Gaganis et al., 2007, Ohno and Nakajin, 2009, Court et al., 2012).