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The metabolism of 17 alpha‐ethinyloestradiol by human liver microsomes: formation of catechol and chemically reactive metabolites.
Author(s) -
Purba HS,
Maggs JL,
Orme ML,
Back DJ,
Park BK
Publication year - 1987
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1987.tb03074.x
Subject(s) - microsome , metabolite , hydroxylation , chemistry , microsoma , metabolism , cytochrome p450 , biochemistry , non competitive inhibition , enzyme , drug metabolism
The metabolism of 17 alpha‐ethinyloestradiol (EE2) to catechol and reactive metabolites by human liver microsomes was investigated. 2‐ Hydroxyethinyloestradiol (2‐OHEE2) was either the sole or principal metabolite. Small amounts of 6‐hydroxyethinyloestradiol and 16‐ hydroxyethinyloestradiol were produced by some of the livers. EE2 (10 microM) underwent substantial (5‐20% of incubated drug), though highly variable, NADPH‐dependent metabolism to material irreversibly bound to microsomal protein. 2‐OHEE2 appeared to be the pro‐reactive metabolite. The maximum EE2 2‐hydroxylase activity was 0.67 nmol min‐1 mg‐1 microsomal protein, with a Km value of 8.6 microM. Oestradiol, which is mainly hydroxylated to 2‐hydroxyoestradiol, was the most potent inhibitor of hydroxylase activity and exhibited competitive inhibition. Progesterone, which undergoes 2‐hydroxylation to a minor extent was also a competitive inhibitor, whereas cholesterol and cortisol did not have any appreciable inhibitory effect. Primaquine was the most potent non‐steroidal inhibitor but was non‐competitive. Other non‐steroidal compounds investigated, e.g. antipyrine, did not show any significant effect on EE2 2‐hydroxylation. The results of this study suggest that EE2 2‐hydroxylation is metabolised by a form(s) of cytochrome P‐450 which has affinity for endogenous steroids.