Until recently, there was little understanding regarding the mechanisms by which substrates are concentrated in bile or regarding what determines the substrate specificity of the transporters. Important questions that have not been addressed, and which are critical for toxicology, relate to the regulation of the activities of these transporters by endogenous, or more importantly, environmental agents. Two examples illustrate the importance of concentrative transport into bile for toxicity and how regulation of this process and the subsequent fate of these conjugates might influence toxicity. In an elegant series of studies, Rickert and colleagues suggested a bioactivation pathway involving hepatic metabolism to dinitrobenzyl glucuronide followed by biliary excretion, deconjugation, and nitroreduction by intestinal microflora, and finally reabsorption of the resulting aminonitrobenzyl alcohol, which was then oxidized to reactive metabolites which were genotoxic. Based on the decreased biliary excretion of many substrates during pregnancy, and following treatment with estradiol, ethinyl estradiol, or diethylstilbestrol, it seems most likely that estrogens are important regulators of phase III elimination.
Estrogens increase gene transcription and secretion of prolactin.
The inhibitory effect of estrogens on the phase III elimination pathway in the rat parallels the decreased bile secretory function seen in normal women in the third trimester of pregnancy and during treatment with estrogen-containing oral contraceptives. However, the female rat liver has an exceptionally high number of prolactin receptors so that the rat may not be a good predictor of the human hepatic response to increased prolactin secretion. A second example illustrates the toxicological importance of hydrolysis of glutathione conjugates following their excretion into bile. The high concentrations of GGT in the intestine and kidney relative to the liver led initially to the concept that these organs were required for formation of cysteine- S conjugates. In the guinea pig, glutathione conjugates are readily hydrolyzed within the biliary tree to the cysteine- S conjugates which can then be reabsorbed from the bile back into the liver.