Inhibition of xenobiotic-metabolizing enzyme

As previously indicated, inhibition of xenobiotic-metabolizing enzymes can cause either an increase or a decrease in toxicity. Several well-known inhibitors of such enzymes are shown in Figure 9.6 and are discussed in this section. Inhibitory effects can be demonstrated in a number of ways at different organizational levels. 

Although the kinetics of inhibition of xenobiotic-metabolizing enzymes can be investigated in the same ways as any other enzyme mechanism, a number of problems arise that may decrease the value of this type of investigation. They include the following ... 

Although examples are known in which synergistic interactions take place at the receptor site, the majority of such interactions appear to involve the inhibition of xenobiotic-metabolizing enzymes. Two examples involve the insecticide synergists, particularly the methylenedioxyphenyl synergists, and the potentiation of the insecticide malathion by a large number of other organophosphate compounds. 

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Agents that selectively induce or inhibit the xenobiotic metabolizing enzymes may alter the toxicity of xenobiotic chemicals. 

Several factors can modulate the activity of xenobiotic-metabolizing enzymes, such as age, the nature of diet, and the presence of disease, but the most important appear to be genetic makeup and concurrent or prior exposure to chemicals (enzyme induction and enzyme inhibition). 

Studies on rats had shown no toxicity of astaxanthin preparations. Dietary administration of astaxanthin has proved to significantly inhibit carcinogenesis in the mouse urinary bladder, rat oral cavity, and rat colon. In addition, it is reported to induce xenobiotic-metabolizing enzymes in rat liver. 

Researchers focused on the metabolically competent human hepatoma cell line HepG2 as a model of human liver. HepG2 cells are a well-known hepatoma cell line that retains many of the morphological characteristics of liver parenchymal cells. This model is often used as a useful tool for HRA/ERA-oriented chemical risk assessment due to the expression of antioxidant and xenobiotic metabolizing enzymes (in particular phase I and phase II enzymes responsible for the bioactivation/detoxification of various xenobiotics) that can be induced or inhibited by dietary and non-dietary agents [28-30]. 

The definition of a poison, or toxicant, also involves a qualitative biological aspect because a compound, toxic to one species or genetic strain, may be relatively harmless to another. For example, carbon tetrachloride, a potent hepatotoxicant in many species, is relatively harmless to the chicken. Certain strains of rabbit can eat Belladonna with impunity while others cannot. Compounds may be toxic under some circumstances but not others or, perhaps, toxic in combination with another compound but nontoxic alone. The methylenedioxyphenyl insecticide synergists, such as piperonyl butoxide, are of low toxicity to both insects and mammals when administered alone but are, by virtue of their ability to inhibit xenobiotic-metabolizing enzymes, capable of causing dramatic increases in the toxicity of other compounds. 

Uncompetitive inhibition has seldom been reported in studies of xenobiotic metabolism. It occurs when an inhibitor interacts with an enzyme-substrate complex but cannot interact with free enzyme. Both Km and Vmax change by the same ratio, giving rise to a family of parallel lines in a Lineweaver-Burke plot. 

This phytochemical has been found to interact with microsomal xenobiotic-metabolizing enzymes in rodents. Capsaicin has been proposed to inactivate cytochrome P-450 HEl by irreversibly binding to the active sites of the enzyme [135]. Besides cytochrome P-450 HEl, other isoforms of the P-450 super family are also reported to be inhibited by capsaicin. The inhibition by capsaicin of microsomal monooxygenases involved in carcinogen activation implies its chemopreventive potential. 

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