**2. CYP450 Class of Enzymes**

The CYP450 monooxygenase system consists of a family of enzymes that metabolize a variety of medications relevant to Cardiology and Oncology. The CYP450 enzymes are primarily located in the liver but can also be found in the small intestines, lungs, kidneys and even the heart [1–4]. These enzymes are responsible for the first pass metabolism and largely explain the higher pharmacokinetic variability of oral drugs compared to intravenous medications [5,6]. Their etymology derives from their intracellular, membrane-bound localization (i.e., cyto-), with a heme pigment forming part of the protein (i.e., chrome). The heme portion of the enzymes absorbs light at a maximum wavelength of 450 nm when complexed with carbon monoxide in the reduced state. In humans, more than 100 collective genes and pseudogenes encode over 50 CYP450 enzymes. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 metabolize over 90% of the substrate drugs and are the most extensively studied CYP450 enzymes [1–3,7] (Table 1).

Drug metabolism in the liver occurs in three major steps: hepatic (transporter-mediated) uptake, phase I reactions and phase II reactions. Hepatic uptake is responsible for a trivial amount of pharmacokinetic variability. In phase I reactions, the CYP450 enzymes oxidize, reduce or hydrolyze their substrates, resulting in loss of pharmacological activity or activation of prodrugs [3]. In phase II reactions, non-CYP450 enzymes conjugate phase I products by adding glucuronide, acetyl, methyl or sulphate groups to form usually inactive polar derivatives for renal or biliary elimination [3,8].


**Table 1.** Most common cytochrome P450 (CYP450) enzymes in humans.

Note: As this is a range, values do not completely sum to 100%. Adapted from [1] with permission.

#### *2.1. Phase I Enzymes*

The most predominant CYP450 enzyme class involved in phase I reactions is the CYP3A family. CYP3A drugs metabolize 45–60% of all drugs currently in use [9,10], with CYP3A4 representing the most common allele. CYP3A4 is predominantly found in the liver [11,12] and intestines [13,14] and can also be found in the stomach, brain, breast and prostate [15]. A second phase I enzyme CYP3A5 is present in the liver and small intestine of 25–30% of individuals [1,3]. A third enzyme CYP3A7 is present predominantly in fetuses (50% of total expression), with expression typically shifting to CYP3A4 in adulthood [1]. CYP1A2 is constitutively expressed primarily in the liver, in significant quantities, measuring up to 16% of the total hepatic P450 pool in some individuals [1]. CYP2C9 is the second most common CYP450 enzyme found in the liver and extrahepatic tissues such as the intestines and endothelial cells; many CYP2C9 substrates (e.g., warfarin) have narrow therapeutic indices, requiring careful monitoring in patients taking these drugs. CYP2C19 is expressed in the liver and kidneys and is responsible for the metabolism clopidogrel, a drug commonly used in cardiology and with relevance for Cardio-Oncology; genetic variation is often associated with adverse drug effects. The CYP2D6 enzyme is primarily expressed outside of the liver and metabolizes approximately 15–25% of drugs from all therapeutic areas, including Cardiology (e.g., beta-blockers, antiarrhythmics) and Oncology (e.g., tamoxifen). There is substantial inter-individual variability with hepatic CYP450 enzyme activity, ranging from 30- to 40-fold variation for collective CYP3A enzymes [16–19] to 100-fold variation for CYP2D6 [16,19].
