section 29.3

Heme Catabolism

693

COOH

HO

F IG U R E 2 9 -1 3

Formation of bilirubin diglucuronide. Glucuronidation occurs in two steps via formation of monoglucuronide. Mono-

and diglucuronides are more water-soluble and less lipophilic than bilirubin. Conversion of bilirubin to water-soluble

products is obligatory for excretion of bilirubin from hépatocytes. M, Methyl; V, vinyl; UPD-GA, UDP-glucuronic acid.

Secretion across the canalicular membrane into bile ap-

pears to be the rate-limiting step in hepatic bilirubin

metabolism. It is probably carrier-mediated, requires en-

ergy, is saturable, and is unaffected by bile salts. Bilirubin

can be made water-soluble by conversion to its configu-

rational isomers. These photobilirubins are formed when

bilirubin is exposed to blue light of the 400- to 500-nm

wavelength (Figure 29-14). Photobilirubins cannot form

the intramolecular hydrogen bonds characteristic of the

natural isomer of bilirubin (Figure 29-12). Thus, they

are more polar and readily excreted in the bile without

the requirement for glucuronidation.

Lumirubin,

a struc-

tural isomer of bilirubin, is formed by light-induced in-

tramolecular cyclization of the vinyl side group of C-3.

It contains a seven-membered ring, is stable, is polar, and

is excreted without conjugation. These observations ex-

plain the mechanism of phototherapy commonly used for

treatment of neonatal hyperbilirubinemia.

F IG U R E 2 9 -1 4

Photoisomers of bilirubin. The presence of two methene bridges containing double bonds (colored areas) gives rise to

configurational (geometrical) isomers of bilirubin. Each double bond can exist in the Z or E configuration. The naturally

occurring, most stable, water-insoluble form is the Z, Z isomer. It undergoes photoisomerization to configurational

isomers (Z, E; E, Z; and E, E), which are more polar owing to inability to form intramolecular hydrogen bonds and are

excretable from the liver without glucuronidation. Some excretion of photoisomers in urine also occurs.