Steric interconversions of atRA occur in vitro and in vivo (Kojima et al., 1994; Marchetti et al., 1997; Sundaresan and Bhat, 1982; Vane et al., 1982; Zile et al., 1967), and the conversion between atRA and 9- and 13-cis RAs alters the available binding forms. Further, glucuronidation is more effective on cis-isomers than on trans-isomers (Genchi et al., 1996; Marchetti et al., 1997), therefore changes in isomerization will alter metabolism and clearance. It is unclear how atRA interconversion is regulated; however, glutathione S-transferases (GSTs) and a variety of sulfhydryl compounds are able to catalyze these reactions (Chen and Juchau, 1997, 1998a,b; Urbach and Rando, 1994a,b). Additionally, retinol saturase converts atROH to at13,14-dihydroretinol (Moise et al., 2005) which can activate transcription through the RAR/RXR heterodimer (Moise et al., 2005). Exposure to TCDD results in decreased levels of glutathione and nonprotein sulfhydryl contents in the liver, through activation of oxidative stress (Shertzer et al., 1998; Stohs, 1990; Stohs et al., 1990). Further, TCDD exposure results in increased GST expression and activity (Aoki, 2001; Safe, 2001). These data suggest that TCDD and the AhR pathway may alter isomerization of atRA in the liver as well, which would influence atRA activity, metabolism, and clearance. However, the ultimate consequence of TCDD and the AhR pathway on RA isomerization is unclear. For example, 9,13-di-cis RA can transactivate through RARa. The production of this isomer could result from reduced trans-cis isomerization (from decreased glutathione and sulfhydryl contents) or from increased cis-trans isomerization (from increased GST expression).

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