Материал из hpluswiki
Перейти к навигации Перейти к поиску

Cytochrome P450 7B1 (24-hydroxycholesterol 7-alpha-hydroxylase) (EC (25/26-hydroxycholesterol 7-alpha-hydroxylase) (EC (3-hydroxysteroid 7-alpha hydroxylase) (Oxysterol 7-alpha-hydroxylase)


CYP7B1-mediated metabolism of dehydroepiandrosterone and 5alpha-androstane-3beta,17beta-diol--potential role(s) for estrogen signaling.

CYP7B1, a cytochrome P450 enzyme, metabolizes several steroids involved in hormonal signaling including 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an estrogen receptor agonist, and dehydroepiandrosterone, a precursor for sex hormones. Previous studies have suggested that CYP7B1-dependent metabolism involving dehydroepiandrosterone or 3beta-Adiol may play an important role for estrogen receptor beta-mediated signaling. However, conflicting data are reported regarding the influence of different CYP7B1-related steroids on estrogen receptor beta activation. In the present study, we investigated CYP7B1-mediated conversions of dehydroepiandrosterone and 3beta-Adiol in porcine microsomes and human kidney cells. As part of these studies, we compared the effects of 3beta-Adiol (a CYP7B1 substrate) and 7alpha-hydroxy-dehydroepiandrosterone (a CYP7B1 product) on estrogen receptor beta activation. The data obtained indicated that 3beta-Adiol is a more efficient activator, thus lending support to the notion that CYP7B1 catalysis may decrease estrogen receptor beta activation. Our data on metabolism indicate that the efficiencies of CYP7B1-mediated hydroxylations of dehydroepiandrosterone and 3beta-Adiol are very similar. The enzyme catalyzed both reactions at a similar rate and the K(cat)/K(m) values were in the same order of magnitude. A high dehydroepiandrosterone/3beta-Adiol ratio in the incubation mixtures, similar to the ratio of these steroids in many human tissues, strongly suppressed CYP7B1-mediated 3beta-Adiol metabolism. As the efficiencies of CYP7B1-mediated hydroxylation of dehydroepiandrosterone and 3beta-Adiol are similar, we propose that varying steroid concentrations may be the most important factor determining the rate of CYP7B1-mediated metabolism of dehydroepiandrosterone or 3beta-Adiol. Consequently, tissue-specific steroid concentrations may have a strong impact on CYP7B1-dependent catalysis and thus on the levels of different CYP7B1-related steroids that can influence estrogen receptor beta signaling.

MeSH Terms

  • Aging
  • Androstane-3,17-diol
  • Animals
  • Cell Line
  • Cytochrome P-450 Enzyme System
  • Dehydroepiandrosterone
  • Estrogen Receptor beta
  • Estrogens
  • Female
  • Gene Expression Regulation
  • Humans
  • Hydroxylation
  • Kinetics
  • Male
  • Organ Specificity
  • Signal Transduction

Expression of key enzymes in bile acid biosynthesis during development: CYP7B1-mediated activities show tissue-specific differences.

The developmental variation of cytochrome P450 (CYP)7A1, CYP7B1, CYP27A1, and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase, key enzymes in bile acid biosynthesis, were investigated in pigs of different ages. As part of these studies, peptide sequences from a purified pig liver oxysterol 7alpha-hydroxylase were analyzed. The sequences showed a high degree of identity with those of murine and human CYP7B1. Enzymatic activities and mRNA levels of CYP27A1 and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase were similar in livers of newborn and 6-month-old pigs. Enzymatic activity mediated by CYP7A1 increased several-fold between infancy and adolescence. Hepatic CYP7A1 and CYP7B1 mRNA levels increased several-fold with age. Hepatic microsomal 7alpha-hydroxylation of 27-hydroxycholesterol and dehydroepiandrosterone, substrates typical for CYP7B1, increased about 5-fold between infancy and adolescence whereas the activities in kidney microsomes decreased at least 10-fold. In conclusion, the results indicate that the expression of CYP27A1 and 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase are similar in livers of newborn and 6-month-old pigs whereas the levels of CYP7A1 increase. The finding that the levels of CYP7B1 increase with age in the liver but decrease in the kidney suggest a tissue-specific developmental regulation of CYP7B1. The age-dependent variation in the liver and kidney suggests that hormonal factors are involved in the regulation of CYP7B1.

MeSH Terms

  • Aging
  • Amino Acid Sequence
  • Animals
  • Animals, Newborn
  • Base Sequence
  • Bile Acids and Salts
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 7
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Kinetics
  • Male
  • Mice
  • Mitochondria, Liver
  • Molecular Sequence Data
  • Orchiectomy
  • Organ Specificity
  • Peptide Fragments
  • Polymerase Chain Reaction
  • Progesterone Reductase
  • RNA, Messenger
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Steroid Hydroxylases
  • Swine
  • Transcription, Genetic