Effects on Xenobiotic Metabolism

Department of Pharmacology and Toxicology, Arkansas Children s Nutrition Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72202 

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

In vivo metabolism and clearance of xenobiotics is the sum of many different processes including (1) the action of many different phase I and II enzymes in the 

Molecular and Biochemical Toxicology, Fourth Edition, edited by Robert C. Smart and Ernest Hodgson Copyright 2008 John Wiley Sons, Inc. 

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Many nutritional effects on xenobiotic metabolism have been noted, but the information is scattered and often appears contradictory. This is one of the most important of several neglected areas of toxicology. This section is concerned only with the effects of nutritional constituents of the diet the effects of other xenobiotics in the diet are discussed under chemical effects (see Section 9.5). 

Because light, temperature, and other in vitro effects on xenobiotic metabolizing enzymes are not different from their effects on other enzymes or enzyme systems,... 

Water-soluble vitamins and co-factors also appear to elicit an effect on xenobiotic metabolism. Ascorbic acid has been shown to inhibit chemically induced chemical carcinogenesis in test systems (Shamberger, ( ). When diets are deficient in choline, the animals appear to become much more susceptible to chemically-... 

DEVELOPMENTAL EFFECTS ON XENOBIOTIC METABOLISM IN NONMAMMALIAN SPECIES... 

Egaas, E., J.U. Skaare, N.O. Svendsen, M. Sandvik, J.G. Falls, W.C. Dautennan, T.K. Collier, and J. Netland. 1993. A comparative study of effects of atrazine on xenobiotic metabolizing enzymes in fish and insect, and of the in vitro phase II atrazine metabolism in some fish, insects, mammals and one plant species. Comp. Biochem. Physiol. 106C 141-149. 

Studies of antipyrine metabolism may be used to illustrate the effect of inhibition on metabolism in vivo in addition, these studies have demonstrated variation among species in the inhibition of the metabolism of xenobiotics. In the rat, a dose of piperonyl butoxide of at least 100 mg/kg was necessary to inhibit antipyrine metabolism, whereas in the mouse a single intraperitoneal (IP) or oral dose of 1 mg/kg produced a significant inhibition. In humans an oral dose of 0.71 mg/kg had no discernible effect on the metabolism of antipyrine. 

Mehrotra K, Morgenstem R, Lundqvist G, et al. 1997. Effects of peroxisome proliferators and/or hypothyroidism on xenobiotic-metabolizing enzymes in rat testis. Chem Biol Interact 104 131-145. 

Jewell C and O Brien NM (1999) Effect of dietary supplementation with carotenoids on xenobiotic metabolizing enzymes in the liver, lung, kidney and small intestine of the rat. British Journal of Nutrition 81,235 2. 

Whitty JP, Bjeldanes LF The effects of dietary cabbage on xenobiotic-metabolizing enzymes and the binding of aflatoxin Bj to hepatic DNA in rats. Food Chem Toxicol 1987 25 581-587. Wattenberg LW Protective effects of 2(3)-tert-butyl 4-hydroxanisole on chemical carcinogenesis. Food Chem Toxicol 1986 24 1099-1102. 

Hoensch HP, Steinhardt HJ, Weiss G, Haug D, Maier A, Malchow H. 1984. Effects of semisynthetic diets on xenobiotic metabolizing enzyme activity and morphology of small intestinal mucosa in humans. Gastroenterology 86 1519-30... 

In addition, analysis of hormone levels in serum samples of white sucker Catostomus commersoni) in Lake Superior have been used to complement measurements of physiological response significant differences in the levels of testosterone and estradiol in females, and of testosterone levels in males have been associated with pollution by bleachery effluents (Munkittrick et al. 1991). It has been observed that feral fish captured from areas exposed to established contamination by PAHs, PCBs, and mercury did not exhibit the increased levels of hydrocortisone normally resulting from capture (Hontela et al. 1992). These results were interpreted as showing the adverse effect on sterol metabolism in fish chronically exposed to such pollutants. Collectively, such data draw attention to the subtler effects of exposure to xenobiotics. 

Moon, Y. J., Wang, X., and Morris, M. E. (2006) Dietary flavonoids effects on xenobiotic and carcinogen metabolism. Toxicol. In Vitro 20, 187-210. 

Washburn, B. S., Vines, C. A., Baden, D. G. et al.. Differential effects of brevetoxin and [beta]-naphthoflavone on xenobiotic metabolizing enzymes in striped bass (Morone saxatilis), Aquat. Toxicol. 35,1, 1996. 

Debersac, P. et al. Effects of a water-soluble extract of rosemary and its purified component rosmarinic acid on xenobiotic-metabolizing enzymes in rat liver. Food Chem. Toxicol, 39,109,... 

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