ABSTRACT:Trichloroethylene (TCE)1 is an important environmental contaminant, a well established rodent carcinogen, and a "probable human carcinogen". Metabolism of TCE occurs primarily via cytochrome P450 (P450)-dependent oxidation. In vitro studies suggested that CYP2E1 is the principal high-affinity enzyme responsible for TCE metabolism. The objective of the present work is to more directly assess the role of CYP2E1 in the metabolism and disposition of 1,2-14 C-TCE administered at 250 or 1000 mg/kg (gavage) using Trichloroethylene (TCE) is a nonflammable solvent that is used as a metal degreasing agent and an ingredient in the manufacturing of glue, paint, and spot removers (Davidson and Beliles, 1991;Gist and Burg, 1995). TCE is a common contaminant of ground and surface water as well as soil and air (Westirck et al., 1984). Owing to its volatility and lipophilicity, TCE is readily absorbed through the lungs and gastrointestinal tract and distributed to various tissues. Exposure to TCE causes a variety of tumors depending on species and tissues (Green, 2000;Clewell and Andersen, 2004). In mice, TCE causes lung and liver tumors after inhalation or gavage exposure (Rhomberg, 2000). Furthermore, exposure to TCE induces kidney and lung toxicity, and inhibits male fertility (Green et al., 1997;DuTeaux et al., 2004;Forkert et al., 2006). Human exposure to TCE was associated with elevated risks of tumors at numerous sites (Raaschou-Nielsen et al., 2002), and was classified as a "probable human carcinogen" (IARC, 1995; NTP, 2002).TCE metabolism occurs via conjugation with glutathione via glutathione S-transferase and oxidation via the cytochrome P450 (P450) enzymes (Lash et al., 2000). glutathione S-transferase-dependent conjugation of TCE is a minor pathway and occurs in the liver and kidney. Subsequent metabolism via the ␤-lyase enzyme leads to the conversion of S-(1,2-dichlorovinyl)-L-cysteine to S-1,2-dichlorovinyl thiol, which is implicated in TCE-induced nephrotoxicity in rats (Elfarra et al., 1986;Lash et al., 2001). Although TCE conjugation is distinguishable from its oxidation in terms of the metabolites produced and target organ specificity, this pathway is not considered quantitatively significant. However, at elevated exposure levels of TCE when the high-affinity oxidative pathway is saturated, the role of conjugation may become more significant (Lash et al., 1998).P450-dependent oxidative metabolism of TCE occurs primarily in the liver and in other organs, such as lung, kidney, and reproductive tract. Although different isozymes (CYP1A1/2, CYP2B1/2, CYP2C11/6, and CYP2E1) have been identified as playing a role in TCE metabolism (Nakajima et al., 1993), CYP2E1 is regarded as a major high-affinity isozyme in the oxidation of TCE. Recent reports showed that CYP2E1, CYP2F, and CYP2B1 are the main enzymes involved in the pulmonary bioactivation of TCE (Forkert et al., 2005(Forkert et al., , 2006. The initial proposed step in the oxidation of this chemical is the conversion to TCE epoxide ( Fig. 1), which may ...

Heterocyclic amines (HCAs) are naturally produced during common cooking processes for meats and fish. HCAs are metabolized by various enzymes, including cytochromes P450, N-acetyl transferases, and sulfotransferases, and their bioactivated metabolites are considered to bind to DNA or protein to show carcinogenic effects. More than 20 HCAs have been identified, of which 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is classified as 'reasonably anticipated to be a human carcinogen' to develop cancers in breast, colon and prostate. The purpose of this study was to evaluate human exposure levels of PhIP and to understand the role of genetic polymorphisms of enzymes on PhIP metabolism. Urine samples were collected from subjects (n = 100) before 3-day meat-restricted diets. Subjects consumed grilled chicken, and their blood and urine were collected before and after the administration of the chickens to investigate genetic polymorphisms and PhIP levels. The mean PhIP levels were 4.22 ± 0.12, 0.61 ± 0.19 and 22.64 ± 1.00 pg ml(-1) in urine under normal conditions and before and after chicken administration, respectively. Among 21 Single-nucleotide polymorphisms (SNP) of CYP1A1, CYP1A2, NATs and UGTs investigated in this study, genotypic groups of CYP1A1/T6235C (MSP I) and CYP1A2/-2467delT showed significant differences in PhIP excretion (P < 0.05). These results suggest that genetic polymorphisms might affect PhIP metabolism, which could improve understanding of populations subject to PhIP-derived health risk.

The levels of persistent organic pollutants (POPs) were determined in 50 samples of Korean human milk. POPs include organochlorine pesticides (OCPs) [aldrin, chlordanes, dieldrin, dichlorodiphenyltrichloroethanes (DDTs), endrins, heptachlors, hexachlorobenzene (HCB), hexachlorocyclohexanes (HCHs), mirex, and toxaphenes] and marker PCBs (PCB28, PCB52, PCB101, PCB138, PCB153 and PCB180). In all samples, p,p'-DDE were determined as 75.5-1115.3 ng/g fat. The compounds β-HCH and p,p'-DDT were detected at 72% and 60% of the samples, respectively. Chlordanes (nd-84.9 ng/g fat) heptachlors (nd-40.1 ng/g fat), HCB (nd-42.9 ng/g fat) and PCBs (nd-38.3 ng/g fat) were detected in several samples. The ratio of dichlorodiphenyltrichloroethylene (DDE)/DDT was 6.8, which explained that exposure of volunteers to DDT did not occur recently. Compared with the previous monitoring data, the level of marker PCBs generally decreased in the milk samples. The levels of OCPs are significantly correlated to the residential periods of the mothers but not with their dietary habits. Considering the daily intake of each OCPs, 18% of infants would ingest the amount of heptachlor exceeding the acceptable daily intake (ADI) proposed by World Health Organization (WHO). There was no sample surpassing the WHO ADI for DDTs, HCB and chlordanes.

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