Biotransformation enzyme induction

Biotransformation Enzyme induction Glutathione S Transferases Mixed Function Oxidases Hydrolases DNA Repair Enzymes... 

Bhuvaneswari, V., Velmurugan, B., and Nagini, S. 2002. Induction of glutathione-dependent hepatic biotransformation enzymes by lycopene in the hamster cheek pouch carcinogenesis model. J Biochem Mol Biol Biophys 6 257-260. 

In order to use PBTK modeling in the assessment of mixtures, Cassee et al. (1998) suggest that one of the components is first modeled and regarded as the prime toxicant being modified by the other components. Based on in vitro data on the other components, effects of, e.g., inhibition or induction of specific biotransformation isoenzymes can be incorporated in the model. Effects of competition between chemicals in a mixture for the same biotransformation enzymes may also be incorporated by translating the effects into effects on the Michaelis-Menten parameters that are then incorporated into the model. 

Batt AM, Siest G, Magdalou J, et al. Enzyme induction by drugs and toxins. Clin Chem Acta 1992 209 109. Bresnick E, Houser WH. The induction of cytochrome P-450c by cytosolic hydrocarbons proceeds through the interaction of a 4S cytosolic binding protein. In Ruckpaul K, Rein H, eds. Frontiers of Biotransformation, Vol. II, Principles, Mechanisms and Biological Consequences of Induction. London Taylor Francis, 1990. 

Enzyme induction The process wherein some drugs provoke cells to synthesize more drug-metabolizing enzymes, thus leading to accelerated drug biotransformation. 

Increased clearance of steroid hormones due to induction of hepatic biotransformation enzymes following chemical exposure often has been cited as a possible mechanism by which toxicants could lower circulating testosterone or 17/3-estradiol levels. While enhanced clearance of sex steroids has been demonstrated following chemical exposure and induction of hepatic biotransformation enzymes, elegant feedback control mechanisms tend to ensure that more hormone is produced and homeostasis is maintained (Figure 17.2). Enhanced clearance of sex steroids can contribute to endocrine disruption if the toxicity also results in impaired hormone synthesis (i.e., gonadal toxicity or interference with the feedback control of hormone synthesis). 2,3,7,8-Tetrachlorodibenzodioxin appears to lower circulating sex steroid levels via this dual effect. 

The rate of biotransformation of a chemical depends on the amount and efficiency of the pertinent biotransformation enzymes. Enzyme activity is partly genetically determined but may also vary between and within people because of enzyme induction caused by previous exposure to the same or related chemicals. Variation in enzyme activity may also be caused by enzyme inhibition due to concurrent exposures. 

Carbamazepine induces CYP3A, and the metabolism of risperidone, which mainly involves CYP2D6, may also involve CYP3A. Carbamazepine can therefore reduce risperidone plasma concentrations (SEDA-22, 71). However, since carbamazepine alters the biotransformation of many agents, non-specific enzyme induction has been suggested for the risperidone and carbamazepine interaction (240). 

Buckman, A.H. Brown, S.B. Small, J. Muir, D.C.G. Parrott, J. Solomon, K.R. Fisk, A.T., Role of temperature and enzyme induction in the biotransformation of polychlorinated biphenyls and bioformation of hydroxylated polychlorinated biphenyls by rainbow trout Oncorhynchus mykiss). Environ Sci. Technol. 2007, 41, 3856-3863. 

Viewed from this angle, a rise in y-GT is a physiological process, i. e. a criterion for increased enzyme induction or a sign of adaptation to the requisite (and accomplished) enhancement in biotransformation performance. 

Early biological effects Initial reactions towards the presence of contaminants Defence mechanisms are a special case of early biological effects. They are either adaptive or defensive reactions and do not represent actual toxic damage. Extrusion of chemicals outside cells by protein pumps Induction of metal-binding proteins or biotransformation enzymes for elimination... 

Monod, G., M.A. Boudry and C. Gillet. Biotransformation enzymes and their induction by beta-naphthoflavone during embryolarval development in salmonid species. Comp. Biochem. Physiol. 114C 45-50, 1996. 

Metals have been shown to dramatically alter CYP concentrations, but there have not been any studies examining the effects on pesticide biotransformation. In contrast, several studies have examined the effects of enzyme induction on pesticide biotransformation. Pre-exposure of channel catfish to the PCB mixture Aroclor 1254 failed to alter the biotransformation of chlorpyrifos or parathion81. As mentioned above, the fungicide propioconizole induced the activation of parathion to the oxon in fathead minnow53. 

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