Hepatic microsomal metabolism of androst-4-ene-3,17-dione: Relative importance of ring hydroxylation and aromatization in control and induced rat liver

1. The liver microsomal metabolism of [4-14C]cholesterol, endogenous cholesterol, 7 α-hydroxy-4-[6 β-3H]cholesten-3-one, 5-β-[7 β-3H]cholestane-3 α, 7 α-diol and [3H]lithocholic acid was studdied in control and clofibrate (ethyl p-chlorophenoxyisobutyrate)-treated rats. 2. The extent of 7 α-hydroxylation of exogenous [414C]cholesterol and endogenous cholesterol, the latter determined with a mass fragmentographic technique, was the same in the two groups of rats. The extent of 12 α-hydroxylation of 7 α-hydroxy-4-cholesten-3-one and 5 β-cholestane-3 α, 7 α-diol was increased by about 60 and 120% respectively by clofibrate treatment. The 26-hydroxylation of 5 β-cholestane-3 α, 7 α-diol was not significantly affected by clofibrate. The 6 β-hydroxylation of lithocholic acid was about 80% higher in the clofibrate-treated animals than in the controls. 3. The results are discussed in the context of present knowledge about the liver microsomal hydroxylating system and bile acid formation in patients with hypercholesterolaemia, treated with clofibrate.

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Further Evidence on the Intramolecular Lactonization in Rat Liver Microsomal Metabolism of 12-O-acetylated Retronecine-type Pyrrolizidine Alkaloids

Natural Product Communications ◽

10.1177/1934578x1300801111 ◽

2013 ◽

Vol 8 (11) ◽

pp. 1934578X1300801 ◽

Cited By ~ 1

Author(s):

Jun Tang ◽

Zhengtao Wang ◽

Teruaki Akao ◽

Masao Hattori

Keyword(s):

Physical Properties ◽

Spectral Data ◽

Rat Liver ◽

Pyrrolizidine Alkaloids ◽

Pyrrolizidine Alkaloid ◽

Liver Microsomes ◽

Rat Liver Microsomes ◽

Microsomal Metabolism ◽

Chromatographic Methods ◽

Transformation Pathway

We have previously found evidence of intramolecular lactonization in rat liver microsomal metabolism of isoline, a 12- O-acetylated pyrrolizidine alkaloid. In this study, the metabolism of another 12- O-acetylated pyrrolizidine alkaloid, acetylduciformine, by the proposed transformation pathway was investigated under the same incubation conditions. Two deacetylated metabolites from acetylduciformine were isolated and purified by chromatographic methods, and further characterized based on their physical properties and spectral data. One metabolite (lankongensisine A) was the lactone of another one (duciformine). Both compounds were first obtained as hydrolyzed metabolites from acetylduciformine by rat liver microsomes. More importantly, the present study provided further evidence for the intramolecular lactonization in the microsomal metabolism of 12- O-acetylated retronecine-type PAs.

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Rat liver microsomal metabolism of o-aminophenol and N-(2-methoxyphenyl)hydroxylamine, two metabolites of the environmental pollutant and carcinogen o-anisidine in humans

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc2010077 ◽

2010 ◽

Vol 75 (12) ◽

pp. 1229-1247 ◽

Cited By ~ 2

Author(s):

Karel Naiman ◽

Petr Hodek ◽

Jiří Liberda ◽

Heinz H. Schmeiser ◽

Eva Frei ◽

...

Keyword(s):

Rat Liver ◽

Dna Adducts ◽

Cytochromes P450 ◽

Environmental Pollutant ◽

Microsomal Metabolism ◽

Human Metabolite ◽

Hepatic Microsomes

o-Aminophenol and N-(2-methoxyphenyl)hydroxylamine are human metabolites of the industrial and environmental pollutant and bladder carcinogen 2-methoxyaniline (o-anisidine). The latter one is also a human metabolite of another pollutant and bladder carcinogen, 2-methoxynitrobenzene (o-nitroanisole). Here, we investigated the ability of rat hepatic micro- somes to metabolize these metabolites. N-(2-methoxyphenyl)hydroxylamine is metabolized by rat hepatic microsomes to o-aminophenol and predominantly o-anisidine, the parent carcinogen from which N-(2-methoxyphenyl)hydroxylamine is formed. In addition, two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, were generated. On the contrary, no metabolites were found to be formed from o-aminophenol by rat hepatic microsomes. Whereas N-(2-methoxyphenyl)hydroxylamine is responsible for formation of three deoxyguanosine adducts in DNA, o-aminophenol seems to be a detoxication metabolite of N-(2-methoxyphenyl)hydroxylamine and/or a parental carcinogen, o-anisidine; no o-aminophenol-derived DNA adducts were found after its reaction with microsomal cytochromes P450 and peroxidases.

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Ring-and N-hydroxylation of 2-acetamidofluorene by rat liver reconstituted cytochrome P-450 enzyme system

Biochemical Journal ◽

10.1042/bj1500561 ◽

1975 ◽

Vol 150 (3) ◽

pp. 561-564 ◽

Cited By ~ 30

Author(s):

P D Lotlikar ◽

K Zaleski

Keyword(s):

Cytochrome C ◽

Rat Liver ◽

Enzyme System ◽

Partial Purification ◽

Hydroxylated Metabolites ◽

Triton X ◽

Cytochrome P 450 ◽

Ring Hydroxylation ◽

Hydroxylation Activity ◽

Nadph Cytochrome C Reductase

The N- and ring-hydroxylation of 2-acetamidofluorene were studied with a reconstituted cytochrome P-450 enzyme from microsomal fractions of liver from both control and 3-methylcholanthrene-pretreated rats. Proteinase treatment and Triton X-100 solubilization were two important steps for partial purification of the cytochrome P-450 fraction. Both cytochrome P-450 and NADPH-cytochrome c reductase fractions were required for optimum N- and ring-hydroxylation activity. Hydroxylation activity was determined by the source of cytochrome P-450 fraction; cytochrome P-450 fraction from pretreated animals was severalfold more active than the fraction from controls. Formation of N-hydroxylated metabolites with reconstituted systems from both control and pretreated animals was greater than that with their respective whole microsomal fractions.

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