Bilirubin photo-isomers: regiospecific acyl glucuronidation in vivo

Abstract

(4Z,15Z)-Bilirubin-IXα, the end product of heme catabolism, requires uridine glucuronosyl transferase 1A1 (UGT1A1)-catalyzed glucuronidation for elimination in bile, where it appears as two isomeric monoglucuronides and a diglucuronide. When people are exposed to light, endogenous bilirubin is converted partly to photo-isomers that are produced in greater abundance during treatment of jaundiced babies with phototherapy. Little is known about the metabolism of the photo-isomers, other than that they appear not to require glucuronidation for elimination in bile. Studies have been hampered by their unavailability and instability, as well as confusion about the identity, structures, preparation, and purity of bilirubin photoproducts. This paper outlines methods for preparing photo-isomers of bilirubins in sufficient quantity and purity for metabolic studies in rats and reappraises the composition of some previous preparations. The studies show that (Z,E)-isomers of bilirubins and the structural isomer (Z)-lumirubin undergo glucuronidation in the rat, but unlike (4Z,15Z)-bilirubin, form only monoglucuronides. Moreover, glucuronidation is regiospecific for just one of the two propionic acid groups, the one attached to the isomerized half of the molecule. This unusual stereoselectivity appears to be dictated by intramolecular hydrogen bonding. Formation of hydroxylated bilirubins was not detected. During phototherapy, photo-isomers will compete with endogenous (4Z,15Z)-bilirubin for glucuronidation by nascent hepatic enzyme UGT1A1.