Rotor's syndrome. A distinct inheritable pathophysiologic entity.

Urinary total, isomer I and isomer III coproporphyrin excretion was determined in 11 patients with Rotor's syndrome, 23 phenotypically normal family members, 16 patients with the Dubin-Johnson syndrome and 20 normal control subjects. Control subjects excreted 24.8 +/- 1.3 per cent (mean SEM) of urinary coproporphyrin as isomer I. Patients with the Dubin-Johnson syndrome excreted 88.9 +/- 1.3 per cent as urinary coproporphyrin I, and patients with Rotor's syndrome excreted 64.8 +/- 2.5 per cent as urinary coproporphyrin I, significantly different from the control subjects and the patients with the Dubin-Johnson syndrome (p less than 0.001). Eight phenotypically normal parents and children of patients with Rotor's syndrome excreted 42.9 +/- 5.4 per cent as urinary coproporphyrin I, intermediate between results in patients with Rotor's syndrome and control subjects (p less than 0.001). Total urinary coproporphyrin excretion was markedly increased in patients with Rotor's syndrome (332 +/- 86 mug/g creatinine) as compared to that in control subjects (p less than 0.001) or obligate heterozygotes (p less than 0.025). With respect to urinary coproporphyrin excretion, Rotor's syndrome and Dubin-Johnson syndrome are both inherited as autosomal recessive traits and are separate pathophysiologic entities. Study of rare but distinct inheritable disorders, such as these, provide insight into the functional dissociation of hepatic transport mechanisms.

A specific glutathione S-transferase isozyme occurring in hereditary hyperbilirubinuria rats.

A glutathione S-transferase isozyme which is absent in normal rat liver has been isolated from the hereditary hyperbilirubinuria rat liver cytosol. The enzyme was purified to apparent homogeneity by GSH-affinity chromatography and HPLC on CM-Sepharose CL-6B. It is a heterodimer of two non-identical subunits, i.e., subunit 2 and a previously uncharacterized subunit referred to here as subunit Yx. Immunoblot analysis indicated that GST 2-Yx belongs to the alpha class. GST 2-Yx is characterized by its 4-fold higher activity towards 4-hydroxy-non-2-enal, compared to that of GST 2-2.

Relevance of urinary coproporphyrin isomers in hereditary hyperbilirubinemias.

Porphyrin metabolism is impaired in Dubin-Johnson syndrome (DJS), Rotor's syndrome (RS), and Gilbert's syndrome (GS). Urinary coproporphyrin (CP) isomer I is increased in these hereditary hyperbilirubinemias to different degrees: in DJS to 85%, in RS to 70%, and in GS to 50% in the homozygous state (p less than 0.001 compared to controls with isomer I of 27%). Intermediate isomer proportions were found in heterozygote carriers of DJS. An overlapping distribution of the isomer I/III ratio is observed in DJS and RS carriers, homozygous subjects with GS, and individuals suffering from alcohol-related intrahepatic cholestasis. The diagnosis of DJS and RS can be based mainly on porphyrin analysis, but the detection of carriers (heterozygotes) requires additional criteria to distinguish them from patients with intrahepatic cholestasis of a different etiology.

[Hyperbilirubinemia]. / Hyperbilirubinämie.

A 22-year-old woman had icteric sclerae since childhood. Five years ago of Gilbert-Meulengracht's disease was diagnosed (hyperbilirubinemia, normal other liver laboratory parameters, no evidence of hemolysis). The patient was admitted for re-evaluation. Apart from jaundice of the sclerae no other clinical symptoms were found. Analysis of urine revealed bilirubin and an increased urobilinogen. Serum bilirubin was also elevated. The differentiation of the bilirubin gave evidence of an increase of the direct (conjugated) bilirubin portion. Additional investigations (total coproporphyrin in the urine, isomer I and isomer III coproporphyrin excretion and bromsulphalein test) suggested Rotor's syndrome. Further examinations (oral cholecystography, liver biopsy) were not added because of relative invasiveness, lack of clinical consequences and opposition of the patient. Nevertheless the diagnosis of a Rotor's syndrome is highly probable.

A new mutant rat with hyperbilirubinuria (hyb).

We have discovered mutant rats with hyperbilirubinuria at the laboratories of Eisai Co., Ltd., Gifu, Japan, and established a new inbred mutant strain, which was designated Eisai Hyperbilirubinuria Rat (EHBR/Eis). They show jaundice immediately after birth, and direct or conjugated hyperbilirubinemia throughout their life. The phenotypes are controlled by a single autosomal recessive gene, hyb with full penetrance. Affected homozygous males seem to have full reproductive capacity. On the other hand, the litter size of hyb/hyb females is significantly reduced at second parturition compared with that at first one. In order to maintain the strain efficiently and to produce both affected (hyb/hyb) and normal control (hyb/+) offspring at the same time, we have mainly been mating hyb/hyb males with hyb/+ females in establishing the inbred strain. We also report here the allele distribution of the EHBR/Eis strain.

Urinary coproporphyrin excretion in Rotor's syndrome: a family study.

A family of seven is described in which a teenage boy and two siblings were found to have Rotor's syndrome. Total urinary coproporphyrin excretion was found to be significantly elevated in the patients with Rotor's syndrome (mean 59 . 0 mumol/mol creatinine), when compared with control subjects (mean 16 . 3 mumol/mol creatinine) (p less than 0 . 005). Similarly, urinary excretion of both coproporphyrin isomer I and coproporphyrin isomer III was greater in the subjects with Rotor's syndrome than in controls (p less than 0 . 005). Coproporphyrin I comprised 60 . 2% of total urinary coproporphyrin excretion in the subjects with Rotor's syndrome, compared with 38 . 6% in the controls, but the difference was not significant. In the parents and clinically unaffected siblings neither total urinary coproporphyrin excretion (13 . 3 and 19 . 3 mumol/mol creatinine respectively) nor percentage coproporphyrin I excretion (36 . 8 and 30 . 4%) differed from controls. Thus, although we have confirmed the previous finding of increased urinary coproporphyrin excretion in subjects with Rotor's syndrome, we have not found the previously noted intermediate increase in coproporphyrin I excretion amongst phenotypically normal relatives of subjects with this autosomal recessive disorder.

Urinary coproporphyrin isomers in Rotor's syndrome: a study in eight families.

Urinary coproporphyrin isomers were measured in 17 patients with Rotor's syndrome, 65 phenotypically normal relatives of 14 patients from eight families, and 21 normal subjects. coproporphyrin I was elevated in Rotor's syndrome (p less than 0.001) and, to a lesser degree, in phenotypically normal parents (p less than 0.005), children, and siblings (p less than 0.025) as compared to normal controls. Coproporphyrin III in patients, parents, and children did not differ from that in normal controls. Genetic analysis was consistent with transmission of Rotor's syndrome as an autosomal recessive trait with respect to urinary excretion of coproporphyrin I. After i.v. injection of delta-aminolevulinic acid, urinary coproporphyrin I increased to a similar extent in Rotor's syndrome and in normal subjects; urinary coproporphyrin III excretion was less in Rotor's syndrome than in normal subjects.

Different biliary excretion systems for glucuronide and sulfate of a model compound; study using Eisai hyperbilirubinemic rats.

The disposition of conjugated metabolites (sulfate and glucuronide) was investigated in Eisai hyperbilirubinemic rats (EHBR) and normal Sprague-Dawley (SD) rats by in vivo and liver perfusion methods. EHBR are mutant rats that have conjugated hyperbilirubinemia as an autosomal recessive trait inheritance, and they show impaired excretion of organic anions into the bile. 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a novel dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, was used as a model compound, because the major metabolites of E3040 are glucuronide and sulfate. After the i.v. injection of [14C]E3040 to EHBR and SD rats, the plasma AUC for glucuronide was greater in EHBR than in SD rats. The cumulative biliary excretion of the glucuronide was impaired to a great extent in EHBR, and the urinary excretion was enhanced. There was no significant difference in the cumulative biliary and urinary excretion of sulfate between EHBR and SD rats. The influx, efflux and sequestration rates of E3040, measured by a multiple indicator dilution method in the perfused rat liver, were similar in EHBR and SD rats. The biliary excretion of the glucuronide formed in the liver, measured by the liver perfusion method, was also severely impaired in EHBR, so the recovery of the glucuronide in the outflow specimens was markedly enhanced. The disposition of the sulfate did not change in either type of rat.(ABSTRACT TRUNCATED AT 250 WORDS)