Barbiturate Enhancement of Bilirubin Conjugation and Excretion in Young and Adult Animals^[35]

Abstract

Extract: Glucuronide conjugation of bilirubin in mammalian liver is catalyzed by the microsomal enzyme uriding phosphoglucuronyltransefrasc (UDPGT). Enzymic activity as measured in vitro is low in the young of many species. The present study was designed to determine whether UDPGT activity could be modified in adult, young, and newborn animals. Following intraperitoneal injection of saline and sodium barbital in control and experimental mice, respectively, for three consecutive days, the UDPGT activity in liver homogenates was measured on the fourth day. A significant increase in the enzyme acctivity was found in all ages. Results (μg bilirubin conjugated/g protein/20 min) include; newborn of dam trated during pregnancy, 96, vs control, 38; 4 days of age, treated (3 groups with 3 different levels of barbiturate for 3 days) 240, 362, and 533, vs control, 186; adult (treated) 181 vs control, 103. These increases were not influenced by adrenalectomy, hypophysectomy, or orchiectomy.

Rabbits also responded with a similar increase in UDPGT activity after pretreatment with phenobarbital given by subcutaneous injection and were utilized in clearance studies. In adult rabbits, following rapid intravenous infusion of bilirubin (8 mg/kg), an enchancement in excretion into bile and an increase in bile flow were observed. Bile flow (μl bile/100 g body weight/min) increased in adult animals following treatment: 2–3 vs control of 1–2. Total bilirubin excreated as a precent of the infused load was: treated, 76% vs control, 33%. In young rabbits, disappearance of bilirubin from serum was faster in the phenobarbital-pretreated animals than in controls. The excretion of bilirubin (Δ bilirubin mg/100 ml serum) in newborn animals was: treated, 3.01; untreated, 1.13. In 4-day-old animals, the excretions was: treated, 3.89 vs controls, 2.61.

It is proposed that several mechanisms may be responsible for the barbiturate effect and they may participate differently at various ages.

Speculation: Barbiturates were found to be effective enhancers of bilirubin conjugation and excretion in animals. A similar approach may have important threapeutic value in the human. Newborn and premature infants with a deficient glucuronide conjugating mechanism and a probable defect in hepatic transport can benefit from this pharamacologic approach. Applicability to patients with hyperbilirubinemia on an inherited metabolic bases also can be considered.

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