Coproporphyrin I and III excretion in bile and urine

Abstract

A B S T R A C T The excretion of coproporphyrin isomers I and III was studied in the rat. Both isomers were found to bind equally to rat plasma and liver cytosol in vitro and to disappear from plasma at equal rates after single injections in vivo. During equimolar infusions of isomers into bile fistula animals, both the I and III isomers were excreted in bile in a concentration ratio of 2: 1, respectively. Pretreatment of animals with ethinylestradiol or simultaneous infusions of phenoldibromophthalein disulfonate caused a reduction in total hepatic excretion with no change in the 2: 1 ratio in bile. As hepatic excretion fell, excretion of both isomers in urine rose, with an increase in the proportion of the I isomer. The findings mimic those reported to occur in man and can be explained by inhibition of a common carrier which requires a stereospecific configuration that statistically favors the hepatic transport of the symmetrical coproporphyrin I isomer.

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

“…CPs I and III are not enzymatically altered in the liver (Kaplowitz et al, 1972), but instead are removed from the body via the bile and urine as intact molecules, albeit unequally. While CP III predominates over CP I in urine, the reverse is encountered in bile (Aziz et al, 1964a,b;French and Thonger, 1966;Koskelo et al, 1967;Aziz and Watson, 1969;Ben-Ezzer et al, 1971).…”

“…Abnormal distribution of CP isomers was reported in the urine of patients with Rotor syndrome, i.e., a marked preponderance of CP I over CP III (Ben-Ezzer et al, 1971;Wolkoff et al, 1976). In addition, administration of ethinylestradiol and phenodibromophthalein disulfonate was shown to result in a reduction in biliary CP excretion and an increase in urinary CP excretion in rats (Kaplowitz et al, 1972). Ethinylestradiol was later found to be a potent inhibitor of OATPs (De Bruyn et al, 2013) and phenodibromophthalein disulfonate also appears to be an OATP inhibitor (Milne et al, 2000).…”

The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man

“…The coproporphyrin isomers I and III leave the body by bile and urine, while the total coproporphyrin excretion into bile is three times the urinary excretion. In healthy persons isomers I and III represent approximately 25% and 75% of total urinary coproporphyrins, and 75% and 25% of total biliary coproporphyrins, respectively [96]. Koskelo et al [97] were the first to report an abnormal urinary coproporphyrin excretion pattern in patients with Dubin-Johnson syndrome, an observation which has since been confirmed in other patients [98,99].…”

“…The mechanism of the abnormal urinary coproporphyrin excretion is not known, although a relationship with a defect in the biosynthesis of hepatic porphyrins was originally postulated [96,98,100]. A defective hepatic uroporphyrinogen III cosynthetase activity would account for a disturbed coproporphyrin type III synthesis and a subsequent shift to the formation of coproporphyrin type I, which might explain the increase of type I in urine.…”

Environmental chemical exposures and disturbances of heme synthesis.

“…Plasma porphyrin concentrations are markedly increased when there are active skin lesions due to any cutaneous porphyria (10 (82). Coproporphyrin normally is excreted in bile and in urine, and impaired biliary excretion in hepatobiliary disease leads to increased coproporphyrin excretion in urine (83). Stimulation of hepatic heme synthesis (e.g., by certain drugs) in the absence of deficiency of any heme-synthesis enzymes can lead to increased coproporphyrin excretion.…”