Glucuronidation and Susceptibility to Chemical Carcinogenesis

Matthew A. Wallig1

Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, Illinois 61802

1 To whom correspondence should be addressed. Fax: (217) 244-7421. E-mail: mawallig{at}uiuc.edu.

Received January 5, 2004; accepted January 5, 2004

ABSTRACT

The highlighted article in this issue of Toxicological Sciences, written by Zhuohan Hu and Peter Wells, addresses a subject that has received increasing scrutiny the past decade and a half—interindividual variation in detoxification enzyme activity as it relates to toxicity and cancer. Hu and Wells in their simple yet elegant study report variations in glucuronidation among normal individuals and provide data that define the potential impact of these variations on covalent binding and cytotoxicity of carcinogenic benzo[a]pyrene (BP) intermediates, gaining in the process important insights into individual potential to resist carcinogenesis by this and related compounds.

The UDP-glucuronosyltransferases (UGT) are important phase II enzymes responsible for conjugating glucuronic acid to a variety of endogenous and exogenous nucleophilic substrates, for example, bilirubin and estrogen (Bock, 1991Go). Despite their participation in a wide variety of phase II conjugation reactions, in particular the glucuronidation of carcinogenic or potentially carcinogenic phenolics, polyaromatic hydrocarbons, and aromatic amines, UGT are sometimes overlooked when the impact of genetic polymorphisms (and hence variations in enzyme activity) among individuals and their susceptibility to cancer are discussed. This is presumably due to that fact that UGT typically metabolize less reactive nucleophilic species rather than the more reactive (and potentially more damaging) electrophilic compounds typically associated with initiation of cancer. Nevertheless alterations in UGT-mediated reactions in an individual due to genetic polymorphisms can have a substantial impact on metabolism and ultimately initiation by altering the flux of various intermediates, carcinogenic and noncarcinogenic, through other detoxification pathways. Glucuronidation has been estimated to account for ~33% of all drugs metabolism by phase II detoxification enzymes (Evans and Relling, 1999Go); therefore, the impact of variations in UGT expression and activity is potentially quite high.

In the past ten years or so a substantial body of literature has developed in which genotypic variation in detoxification enzyme systems has been investigated and then related to susceptibility to various cancers. Although much of the focus on genetic polymorphisms and their impact on toxicity and carcinogenesis has been centered on the cytochrome P450 and glutathione S-transferase groups of enzymes, UGT polymorphisms in relation to enhanced susceptibility to toxicity and cancer have received increasing attention in the past five years, as recently reviewed by Guillemette (2003)Go. From these studies it has become increasingly apparent that variations in UGT genotype, either through polymorphisms in promoter alleles or single nucleotide polymorphisms, are associated with altered risk to certain cancers such as pancreatic cancer and breast cancer, to name just two (Guillemette et al., 2000Go; Ockenga et al., 2003Go).

As with polymorphisms in other detoxification enzyme systems, however, the association between genotype and cancer incidence has generally been weak or even nonexistent in many cases, and further complicated by factors such as race, prior drug therapy, concomitant polymorphisms in other enzyme systems, and—most consistently of all—smoking history (for example, Zheng et al., 2001Go). As has been observed with other enzyme systems, smoking history would appear to be the most consistent feature in the association between low activity genotypes and susceptibility to cancer; that is, in individuals without a history of smoking, the association between UGT genotype and cancer susceptibility is generally weak or absent while the opposite is true for smokers.

In contrast to the rapidly expanding literature addressing links and associations between genotype and cancer susceptibility, there is a much smaller body of literature addressing how phenotypic variation in detoxification activity among individuals affects metabolism and inactivation of specific carcinogens and virtually no reports linking UGT genotype, UGT phenotype, and susceptibility to cancer. In particular, studies addressing glucuronidation among normal individuals and how that variation might predispose to toxicity or cancer are surprisingly sparse.

The study by Hu and Wells is an initial step in filling this gap, for in it are data that clearly identify striking individual variations in UGT activities against the prototype carcinogen, benz(a)pyrene (BP), data that correlate convincingly individual capacity for glucuronidation with ability to decrease covalent binding and cytotoxicity of carcinogenic BP metabolites. For their model Hu and Wells use lymphocytes from twelve normal human volunteers to assess the overall capacity of these individuals to metabolize BP and thereby prevent covalent binding to macromolecules and subsequent cytotoxicity. Basing their use of lymphocytes on previous work showing that UGT metabolism of BP in lymphocytes is an accurate reflection of UGT metabolism in liver (Hu and Wells, 1994Go), they incubated lymphocytes with reactive BP intermediate metabolites normally glucuronidated by UGT, measuring the resultant glucuronide metabolites as well as assessing covalent binding and cytotoxicity. Besides finding wide variation in glucuronidation (up to 200-fold) among individuals, the authors discovered strong negative correlations between the capacity to glucuronidate and/or the amount of covalent binding and the degree of cytotoxicity by toxic BP intermediates, specifically for BP diols and diones. The inevitable conclusion that they draw is that normal individuals with low glucuronidation may be at increased risk for cancer caused by polyaromatic hydrocarbons that rely on glucuronidation for inactivation. The novelty of this study is that it is not only the first direct evidence for substantial interindividual variation among normal individuals in the metabolism of BP but it also confirms findings in animal models that glucuronidation can indeed modulate and presumably protect tissues from damage by reactive BP metabolites.

As in any good study, the results of this particular work pose as many questions as they provide answers. For starters, specific UGT polymorphisms were not delineated in the individuals studied and hence potential associations, correlations, and links between genotype and phenotype were not identified, something that is very much lacking in the literature overall. In addition, the various the cytochrome P450 and glutathione S-transferase phenotypes of the individuals in this study were not assessed, leaving open the question of the impact multiple polymorphisms on the responses of the various individuals to the BP metabolites. Indeed, there is evidence that polymorphisms and the subsequent variations in phenotype in several enzyme systems, rather than any one system alone, may be the most important determinant of susceptibility to cancer (Dialyna et al., 2003Go). Finally, a cautionary note must be made with regards to associating certain UGT genotypes and phenotypes with protection against chemical carcinogenesis—increased glucuronidation may be a double-edged sword in some situations since it has been shown that bacterial glucuronidases in the colon can result in the deconjugation of reactive metabolites, enhancing the potential for carcinogenesis in the colon. In similar fashion, the pH environment of human urine is also conducive to deglucuronidation of metabolites increasing the risk of bladder cancer (Bock, 1991Go; Taningher et al., 1999Go). Confounding factors such as these will have to be taken into account with any study undertaken to correlate individual susceptibility to chemical carcinogenesis and enzyme expression. Nevertheless, the findings of Hu and Wells open up exciting possibilities in the efforts to accurately determine individual risk from exposure to carcinogens.

REFERENCES

Bock, K. W. (1991). Roles of UDP-glucuronosyltransferases in chemical carcinogenesis. Crit. Rev. Biochem. Mol. Biol. 26, 129–150.[Abstract]

Dialyna, I. A., Miyakis, S., Georgatou, N., and Spandidos, D. A. (2003). Genetic polymorphisms of CYP1A1, GSTM1 and GSTT1 genes and lung cancer risk. Oncol. Rep. 10, 1829–1835.[ISI][Medline]

Evans, W. E., and Relling, M. V. (1999). Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286, 487–491.[Abstract/Free Full Text]

Guillemette, C. (2003). Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J. 3, 136–158.[CrossRef][ISI][Medline]

Guillemette, C., Milliken, R. C., Newman, B., and Housman, D. E. (2000). Genetic polymorphisms in uridine diphospho-glucuronosyl transfersae 1A1 and association with breast cancer in African Americans. Cancer Res. 60, 950–956.[Abstract/Free Full Text]

Hu, Z., and Wells, P. G. (1994). Modulation of benzo(a)pyrene bioactivation by glucuronidation in peripheral blood lymphocytes from rats with a genetic deficiency in bilirubin UDP-glucuronosyltransferases. Toxicol. Appl. Pharmacol. 127, 306–313.[CrossRef][ISI][Medline]

Ockenga, J., Vogel, A., Teich, N., Keim, V., Manns, M. P., and Strassburg, C. P. (2003). UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology 124, 1802–1808.[CrossRef][ISI][Medline]

Taningher, M., Malacarne, D., Izzotti, A., Ugolini, D., and Parodi, S. (1999). Drug metabolism polymorphisms as modulators of cancer susceptibility. Mutat. Res. 436, 227–261.[CrossRef][ISI][Medline]

Zheng, Z., Park, J. Y., Guillemette, C., Schantz, S. P., and Lazarus, P. (2001). Tobacco carcinogen-detoxifying enzyme UGT1A7 and its association with orolaryngeal cancer risk. J. Natl. Cancer Inst. 93, 1411–1418.[Abstract/Free Full Text]