Human Drug Metabolism

Sites of biotransforming enzymes (Drug Biotransformational Systems – Origins and Aims) (Human Drug Metabolism)

Aside from their biotransformational roles in steroid biosynthesis and drug/toxin clearance, CYPs carry out a wide array of metabolic activities that are essential to homeostasis. This is not surprising, as they are found in virtually every tissue. The main areas are the liver and gut that have the highest concentrations of biotransformational capability. These CYPs […]

Biotransformation and xenobiotic cell entry (Drug Biotransformational Systems – Origins and Aims) (Human Drug Metabolism)

Role of the liver Drugs, toxins and all other chemicals can enter the body through a variety of routes. The major route is through the digestive system, but chemicals can by-pass the gut via the lungs and skin. Although the gut metabolizes many drugs, the liver is the main biotransforming organ and the CYPs and […]

Capture of lipophilic molecules (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Introduction It is essential for living systems to control lipophilic molecules, but as mentioned earlier, these molecules can be rather ‘elusive’ to a biological system. Their lipophilicity means that they may be poorly water-soluble and may even become trapped in the first living membrane they encounter. To change the physicochemical structure and properties of these […]

Cytochrome P450s: classification and basic structure (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

CYPs belong to a group of enzymes which all have similar core structures and modes of operation. Although these enzymes were discovered in 1958, vast amounts of research have not yet revealed all there is to know of their structure and function. Their importance to us is underlined by their key role in more than […]

CYPs – main and associated structures (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

General structure There are many complex and detailed three-dimensional structures of the CYPs available online which are worth viewing. However, there is perhaps a simpler way to help you visualize some idea of CYP flexibility and structure at the same time. If you place a small coin a little off centre of the palm of […]

Human CYP families and their regulation (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

As we have seen, despite their common structure and function, CYP substrate specificity varies enormously within the main families of these enzymes. Aside from CYPs that are involved in steroid synthesis and arachidonic acid metabolism, there are only three CYP families which are relevant to humans in terms of drug and toxin biotransformations. These include: […]

Main human CYP families (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

CYP 1A series CYP1A1 The gene that codes for CYP1A1 is on chromosome 15. This isoform binds and oxidizes planar aromatic, essentially flat, lipophilic molecules. The most common representatives of these compounds are multiples of benzene, such as naphthalene (two benzenes), and what are usually termed polycyclic aromatic hydrocarbons (PAHs) that are many benzene molecules […]

Cytochrome P450 catalytic cycle (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Having established the phenomenal multiplicity and flexibility of these enzymes, it should be a relief to learn that all these enzymes essentially function in the same way, although again we do not fully understand the process yet. CYPs can carry out reductions (see later on) and these occur after substrate binding and before oxygen binding. […]

Flavin Monooxygenases (FMOs) (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

Introduction Alongside the CYPs, other cellular systems can accomplish oxidations of endogenous molecules and these systems are usually widespread in many tissues. Of these systems, the flavin monooxygenases (FMOs) have not received anything like the attention directed at CYPs, although realization of their significance in drug clearance is growing rapidly. Originally known as ‘Ziegler’s enzyme’, […]

How CYP isoforms operate in vivo (How Oxidative Systems Metabolize Substrates) (Human Drug Metabolism)

The detailed processes on how living systems operate are sometimes focused on at the expense of a global understanding of how these systems might operate in the tissue. It is useful to try to visualize how CYPs process massive numbers of molecules from hydrophobic to at least partially hydrophilic products every second. If you visualize […]

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