Factors that contribute to xenobiotic metabolism
Considering the complexity of xenobiotic metabolism, different factors may affect the occurrence of enzymatic reactions. Different taxa often vary widely in their responses to toxic compounds and even similar metabolism rates of a compound may result in different products. Within an animal species there are also strain differences in xenobiotic-metabolizing processes. Moreover, interindividual genetic and epigenetic variability in the ability to carry out certain biotransformations by unfunctional or absent particular enzymes that determine such adverse responses has been shown to influence chemical efficacy and toxicity directly. Reactive intermediates may bind to DNA and disrupt the normal expression rate of several xenobiotic-metabolizing enzymes, resulting in an increment of cellular response variability.
In addition to genetic differences between species or strains, metabolisms may be further altered by physiological factors such as gender and age. Males and females may differ in their response to toxic compounds, due to metabolic and hormonal differences. Depending on the age and stage of development, the rate of metabolism and susceptibility to toxic compounds may differ. In humans, there is evidence that the elderly have a decreased rate of hepatic microsomal metabolism of some compounds. Also, the activity of microsomal and nonmicrossomal xenobiotic-metabolizing enzymes is low in premature and neonatal infants, as most mechanisms are only developed at later stages.
Environmental factors can introduce as much variation in xenobiotic in drug metabolism as can genetic factors, and this is especially true for drug-drug interactions.
Another factor of major concern is the modification of xenobiotic metabolism by temporary stimulation or inhibition, particularly related with chemical exposure. The changes in xenobiotic metabolism can be in either positive or negative directions, involving one single isozyme and a single reaction or can be generalized over many enzymes catalyzing many different reactions.
Some toxic effects may be also related to the deficiency of essential nutrients or vitamins, by decreasing xenobiotic metabolism. Diets supplemented with the nutrients can increase chemical metabolism above normal.
2.1 Induction of xenobiotic-metabolizing enzymes
The stimulation of enzyme activity as a result of the increased amount of the enzyme present is referred as induction. The term activation is use in cases of efficiency increment of an existing enzyme.
An exposure to a wide range of chemicals can increase the activity of many microsomal and some cytoplasmatic xenobiotics-metabolizing enzymes. Generally, these chemicals are lipophilic and persistent into the organism. Some of the induction activity has been attributed to a stabilization of an existing enzyme in addition to the formation of a new enzyme either via enhanced mRNA transcription or changes in the translation rate of basal amounts of mRNA.
Although the cytosolic GSH transferases are induced by a wide range of agents, nonmicrossomal enzymes are not induced as extensively as microsomal enzymes. An induction of phase I enzymes does not necessarily leads to an increase in the induction of phase II enzymes, from which results an imbalance in the ability of phase II reactions to conjugate all the reactive centers generated by the enhanced phase I activity. Sometimes, phase II enzyme activities are increased with little effect in phase I enzymes.
An inducing substance may increase the metabolism of one or more endo- and xenobiotics and can also increase its own metabolism. Altering the balance between phase I and phase II reactions, some increased toxicity may occur.
2.2 Inhibition of xenobiotic-metabolizing enzymes
Taking into account the presence of several but relatively nonspecific xenobiotics-metabolizing enzymes, many chemicals often share structural similarities that facilitate competition for the same active site of the enzymes. By acting as a competitive inhibitor, these chemicals block the access by the substrate to the active site of the enzyme, preventing its biotransformation and a mutual inhibition of their own metabolism may also occur (Figure 14b).
Figure 14 - Inhibition of xenobiotic-metabolizing enzymes. (a) Normal binding; (b) Competitive inhibition; (c) Noncompetitive inhibition.
Source: http://image.slidesharecdn.com/08lecture-141005184902-conversion-gate01/95/08-lecture-intro-to-metabolism-66-638.jpg?cb=1412553072
Inhibitors can be extremely selective
for the enzyme or isozyme they exert effect on. Moreover, since
xenobiotic metabolism is catalyzed by enzymes, many non-competitive
inhibitors protein denaturants (heavy-metal ions, detergents...) can
inhibit non-selectively these reactions by altering structurally and
spatially the geometry of the enzyme active site and hence diminishing
its affinity and access for the substrate (Figure 14c).
The beneficial or adverse effects resulting from inhibition of xenobiotic-metabolizing enzymes depend on the perspective from which it is viewed. Some inhibitors have important applications as pesticide (piperonylbutoxide, organophosphates), fungicide (clotrimazole), etc.
See the following video to better understand the competitive and non-competitive inhibition process of xenobiotic-metabolizing enzymes:
https://www.youtube.com/watch?v=PILzvT3spCQ
CASE STUDY
Abcb4 acts as multixenobiotic transporter and active barrier against chemical uptake in zebrafish (Danio rerio) embryos. Ficher et al. (2013):
http://www.biomedcentral.com/content/pdf/1741-7007-11-69.pdf
REFERENCES
Burcham PC. (2014). An Introduction to Toxicology. 1st edition. Springer-Verlag, London. 338p.
Eaton DL, Gallagher EP. (2010). Comprehensive Toxicology. 2nd edition. Elsevier Ltd., University of Washington, Seattle, WA, USA. 6837p.
Hodgson E. (2010). A textbook of modern toxicology. 4th edition. John Wiley & Sons, Inc., Hoboken, New Jersey. 648p.
Klaassen CD. (2008). Casarett and Doull's Toxicology. The Basic Science of Poisons. 8th edition. McGraw-Hill Education, LLC, New York, USA. 1454p.
Luckenbach T, Fischer S, Sturm A. (2014). Current advances on ABC drug transporters in fish. Comparative Biochemistry and Physiology, Part C 165: 28-52.
Scholz S, Fischer S, Gündel U, Küster E, Luckenbach T, Voelker D. (2008). The zebrafish embryo model in environmental risk assessment - applications beyond acute toxicity testing. Environmental Science Pollution Research 15: 394-404.
Stelljes ME. (2008). Toxicology for Non-toxicologists. 2nd edition. The Scarecrow Press, Inc, Lanham, Maryland, USA. 207p.
terBeek J, Guskov A, Slotboom DJ. (2014). Structural diversity of ABC transporters. The Journal of General Physiology 143: 419-435.
Online resources
https://www.youtube.com/watch?v=PILzvT3spCQ
http://www.biomedcentral.com/content/pdf/1741-7007-11-69.pdf
