Metabolism of Bisphenol A in Primary Cultured Hepatocytes from Mice, Rats, and Humans

Studies have shown that in the rat, bisphenol A (BPA) is metabolized and eliminated primarily as a monoglucuronide, a metabolite without estrogenic activity. The purpose of this study was to determine the extent of monoglucuronide formation in monolayers of hepatocytes from rats, mice, and humans. Noncytotoxic concentrations of BPA (10, 20, and 35 microM; 1.0 microCi), as assessed by lactate dehydrogenase leakage, were incubated with isolated hepatocytes for 0-6 h. Media were collected and analyzed for metabolites by radiochemical high performance liquid chromatography and liquid chromatography-tandem mass spectrometry. The metabolites identified include a monoglucuronide (major metabolite), a sulfate conjugate, and a glucuronide/sulfate diconjugate (minor metabolites). In hepatocytes of male Fischer-344 rats, the predominate metabolite was the diconjugate (glucuronide/sulfate). Under these conditions, the extent of metabolism by 3 h was similar in all species tested because all BPA was converted to conjugates by 3 h. Initial rates of metabolism in hepatocytes followed the order of mice > rats > humans. However, when extrapolated to the whole liver (i.e., cells per liver), the hepatic capacity for BPA glucuronidation is predicted to be humans > rats > mice. This research was supported in part by The Society of Plastics Industry Inc., and Southwest Environmental Health Science Center (ES 06694).