The human UGT1A3 enzyme conjugates norursodeoxycholic acid into a C23-ester glucuronide in the liver.

Norursodeoxycholic acid (norUDCA) exhibits efficient anti-cholestatic properties in an animal model of sclerosing cholangitis. norUDCA is eliminated as a C(23)-ester glucuronide (norUDCA-23G) in humans. The present study aimed at identifying the human UDP-glucuronosyltransferase (UGT) enzyme(s) involved in hepatic norUDCA glucuronidation and at evaluating the consequences of single nucleotide polymorphisms in the coding region of UGT genes on norUDCA-23G formation. The effects of norUDCA on the formation of the cholestatic lithocholic acid-glucuronide derivative and of rifampicin on hepatic norUDCA glucuronidation were also explored. In vitro glucuronidation assays were performed with microsomes from human tissues (liver and intestine) and HEK293 cells expressing human UGT enzymes and variant allozymes. UGT1A3 was identified as the major hepatic UGT enzyme catalyzing the formation of norUDCA-23G. Correlation studies using samples from a human liver bank (n = 16) indicated that the level of UGT1A3 protein is a strong determinant of in vitro norUDCA glucuronidation. Analyses of the norUDCA-conjugating activity by 11 UGT1A3 variant allozymes identified three phenotypes with high, low, and intermediate capacity. norUDCA is also identified as a competitive inhibitor for the hepatic formation of the pro-cholestatic lithocholic acid-glucuronide derivative, whereas norUDCA glucuronidation is weakly stimulated by rifampicin. This study identifies human UGT1A3 as the major enzyme for the hepatic norUDCA glucuronidation and supports that some coding polymorphisms affecting the conjugating activity of UGT1A3 in vitro may alter the pharmacokinetic properties of norUDCA in cholestasis treatment.

[Single-hormone prophylaxis of uterine hemorrhages in the premenopause]. / Monokhormonalna profilaktika na matochnite kruvotecheniia v premenopauzata.

Single-hormone prophylaxis with gestagen (Primolut nor) was carried out on 62 women with uterine bleedings during the premenopause of climacteric at mean age of 46.8 years. A ten-day scheme with application of 5 mg of gestagen daily from 16 to 25 day of the cycle for a period of 6 months was used. The treatment provided stable clinical characteristic of the successive pseudomenstrual cycles could continue for a considerable time practically till disappearance of pseudo-menstruation and transition of the woman in postmenopause. Primolut nor was a convenient drug also in women under continuous anticoagulant treatment. However it was effective and could not be used for treatment of accompanied climacteric symptoms.

[Restoration of the reproductive function in dysfunctional uterine hemorrhage patients under gestagenic steroid treatment]. / Vosstanovlenie reproduktivnoi funktsii u bol'nykh s disfunktsional'nymi matochnymi krovotecheniiami pri lechenii gestagennymi steroidami.

PIP: A study was made of the possibility of restoration of reproductive function in patients with dysfunctional uterine hemorrhage during the reproductive period by various steroids--nortestosterone derivatives (norsteroids) and progesterone derivatives. There were 73 patients with dysfunctional uterine hemorrhages, all of whom were sterile. Ovulation was stimulated in 61 cases, and pregnancy occurred in 32 (37.7%). (Author's modified)^ieng