Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and micein vitro

Abstract

1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.

Human phase I in vitro liver metabolism of two bisphenolic diglycidyl ethers BADGE and BFDGE

“…These data suggest a rapid hydrolysis of BADGE to BADGE.2H2O when exposed to microsomal fractions. This confirms earlier findings by Bentley et al, Boogaard et al and Climie et al (10,11,17) The hydrolysis appears to be NAPDH independent as it occurred also in the negative control samples where the cofactor NAPDH had been omitted. Boogaard et al stated that this hydrolysis was J o u r n a l P r e -p r o o f catalyzed by epoxide hydrolase, an enzyme class which does not need a cofactor, which agrees to the findings of our study.…”

“…Earlier studies have investigated the inactivation and distribution of glycidyl ethers in various tissues of rats, mice and humans, but always tended to focus on the hydrolysis products of the epoxide moieties, BADGE.2H2O and BFDGE.2H2O. (10)(11)(12) Given the fact that the hydrolysed derivatives of BADGE and BFDGE can be easily formed when in contact with aqueous and acidic foodstuff, they can readily be present in canned foods. In addition they have also been detected in indoor dust and as a result cannot be solely used to monitor human exposure to BADGE and BFDGE.…”

Widespread Occurrence and Distribution of Bisphenol A Diglycidyl Ether (BADGE) and its Derivatives in Human Urine from the United States and China

“…In addition to the direct intake of BADGE·2H 2 O from foods, in vivo metabolism of BADGE and other precursors can contribute to the formation of BADGE·2H 2 O in human bodies. 15,16,19,20 The proportion of BADGE·-H 2 O·HCl is relatively low, especially in urine from China, indicating a lower level of chloride derivatives of BADGEs in human urine. Creatinine also was determined in urine samples from the U.S. and China.…”

In Vitro Metabolism of 8-2 Fluorotelomer Alcohol: Interspecies Comparisons and Metabolic Pathway Refinement

“…Similar equations were used to calculate microsomal intrinsic clearance using the amount of protein (milligrams) in the incubation system, giving CL I in units of ml/min/mg protein. The values for liver were 35, 49, and 58 mg microsomal protein/gram of tissue for mouse (Csanády et al, 1992;Medinsky et al, 1994), rats (Baarnhielm et al, 1984;Boogaard et al, 2000;Chiba et al, 1990;Csanády et al, 1992;Joly et al, 1975), and humans (Baarnhielm et al, 1986;Boogaard et al, 2000;Csanády et al, 1992;Lipscomb et al, 2003a,b), respectively. Multiplying this value by the grams of liver weight per kilograms of body weight and milligrams of protein per gram of liver converted the CL I in units to ml/min/kg.…”