Is serum gamma-glutamyltransferase a biomarker of xenobiotics, which are conjugated by glutathione?

A meta-analysis of 10 prospective cohort studies,1 including our own,2 reported that serum -glutamyltransferase (GGT) predicted incident vascular events. This metaanalysis posed one important, but unsolved question: why does serum GGT predict incident vascular events? In addition to vascular events, serum GGT predicts various important clinical outcomes including type 2 diabetes, metabolic syndrome, and renal problems.3–5 Serum GGT has traditionally been used as a marker of alcohol consumption; however, alcohol consumption cannot explain the disease relationships with serum GGT because these associations have been observed among nondrinkers as well as drinkers. The other prevailing interpretations are that serum GGT predicts clinical outcomes as a marker of nonalcoholic fatty liver disease (NAFLD) or oxidative stress.6–8 Although both of these explanations have some merit, each also has problems. Although not clearly stated in many of the reports,1–5 most associations of serum GGT with clinical outcomes were dose-response relations within the normal range of serum GGT; we submit that this aspect of the association is critical to interpretation. First, even though NAFLD may partially explain the associations among subjects with a relatively high serum GGT activity and NAFLD can present even among subjects with low normal serum GGT, NAFLD is unlikely to fully explain the graded associations with clinical outcomes which were observed among subjects with serum GGT in the low part of its normal range, less than 20 or 30 U/L. However, it is worthwhile to note that serum GGT may be a predictor of the future risk of NAFLD. In a prospective study by our group,9 serum GGT within its normal range strongly predicted the future risk of chronic elevation of serum alanine aminotransferase (ALT), but serum ALT within its normal range did not predict the future risk of chronic elevation of serum GGT. The most common reason for elevated serum ALT, especially among nondrinkers, is NAFLD.10 We refer to this issue below in relation to xenobiotics. Several years ago our research group proposed that serum GGT within its normal range should be regarded as a marker of oxidative stress,11 as seen from two contrary perspectives. As a primary function, cellular GGT metabolizes extracellular glutathione (GSH) to allow precursor amino acids to be assimilated and reused for intracellular GSH synthesis. Thus, cellular GGT can be seen as an antioxidant enzyme because increased cellular GGT favors the supply for intracellular GSH, the most important intracellular antioxidant. On the other hand, cellular GGT can be involved in the generation of oxidative stress in the presence of transition metals. Even though the direct relation between cellular GGT and serum GGT under the physiological condition is unclear, serum GGT has been assumed to reflect these properties of cellular GGT. However, the concept of serum GGT as primarily either an antioxidant or a pro-oxidant marker presents a challenge in understanding the GGT and disease relationships. As an antioxidant marker, even though the initial increase of GGT may be compensatory to depleted GSH because of oxidative stress, serum GGT would be expected to decrease the risk of clinical outcomes because the parallel increase in cellular GGT would lead to increased intracellular GSH. However, epidemiological studies contradict this, consistently reporting serum GGT within its normal range predicts increasing risk of various clinical outcomes. From the opposite perspective, it is difficult to believe that pro-oxident effects of GGT would occur across the low normal range of serum GGT in vivo, considering that GGT is indispensable in metabolizing GSH, an essential component in the cell.12 Although we do not exclude the possibility that GGT itself can be involved in generating oxidative stress in vivo, this too seems unlikely to be a significant factor across the low normal range of GGT. A potentially interesting interpretation subsumes GGT as a biomarker of exposure to xenobiotics. We have recently reported that some environmental pollutants such as lead, cadmium, dioxins, or organochlorine pesticides are positively and monotonically related to serum GGT in the general population without any occupational exposure.13,14 Interestingly, the associations between environmental pollutants and serum ALT, a more liver specific enzyme and more commonly used as a marker of NAFLD than serum GGT, were opposite to those of serum GGT, suggesting that the associations of serum GGT may not be related to liver toxicity. Indeed, GSH has a very important function in conjugating xenobiotics to facilitate their excretion. In general, metabolism of xenobiotics consists of phase I and phase II reactions.15 In phase I, xenobiotics are generally converted to more polar, hydroxylated derivatives. In phase II, these derivatives are conjugated with molecules such as glucuronic acid, sulfate, or GSH. This renders them more water-soluble, facilitating excretion in the urine or bile. GSH conjugates From the Department of Preventive Medicine (D.-H.L.), School of Medicine, Kyungpook National University, Daegu, Korea; the Division of Epidemiology (D.R.J.) and the Department of Laboratory Medicine and Pathology (M.D.G., M.W.S.), School of Public Health, University of Minnesota, Minneapolis; and the Department of Nutrition (D.R.J.), University of Oslo, Norway. Correspondence to Duk-Hee Lee, MD, PhD, Department of Preventive Medicine, School of Medicine, Kyungpook University, 101 Dongindong, Jung-gu, Daegu, Korea 700-422. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2008;28:e26-e28.) © 2008 American Heart Association, Inc.