Liver biotransformation processes

With respect to drug-metabolizing enzymes, the majority of the CYPs responsible for phase I metabolism are concentrated in liver. The CYPs considered here are all found in the endoplasmic reticulum (isolated as microsomes ). Of the 18 human CYP families known, the bulk of xenobiotic biotransformation processes are carried out by enzymes from the CYP1, CYP2 and CYP3 families. In humans, realistically,... 

This biotransformation process takes place principally in the liver, i.e. in the smooth endoplasmic reticulum, partly also in the mitochondria. The kidneys, lungs, intestine, muscles, spleen and skin are involved to a lesser degree in biotransformation. Through hydrolysis and reduction, the intestinal flora may also play a role in this metabolic process. Biotransformation is limited by the hepatic blood flow (= flow-limited elimination) and by the capacity of microsomal enzyme systems (= capacity-limited elimination). (80, 95)... 

Tong and Lien reported significant correlation between the inhibition of beef-heart submitochondrial NADH oxidation by 14 barbiturates and their corn oil-water partition coefficient. However, when the data for stimulation of rat liver microsomal NADPH oxidation by the same barbiturates were correlated, a good correlation was observed only after exclusion of 5-allylbarbiturates, which indicates different activity of the allyl group in this biotransformation process.542 The relationship between molecular structure and duration of depressant effect for 160 5,5-disubstituted barbiturates was investigated by the so-called Pattern Recognition Technique. The results were consistent with those obtained via the Hansch approach.543... 

A variety of chemicals modify biotransformation processes (9). Among these are a number of organochlorlnc pesticides, such as DDT, which Induce liver enzyme activites. In general, such pesticides Inhibit the carcinogenicity to experimental animals of activation-dependent carcinogens. 

Other relevant metabolic pathways result in detoxified substances, such as biotransformation processes in the liver — conjugation wifli glycine, glucuronic acid and sulphuric acid (e.g., via hydroxylation of toluene) or biotransformation by hydrolysis, oxidation and conjugation (e.g., glycol ethers). 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

The liver is the dominant organ in the detoxification process. The detoxification occurs by biotransformation, in which the chemical agents are transformed by reaction into either harmless or less harmful substances. Biotransformation reactions can also occur in the blood, intestinal tract wall, skin, kidneys, and other organs. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

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