Hydroxylation of acetone by ethanol‐ and acetone‐inducible cytochrome P‐450 in liver microsomes and reconstituted membranes

Johansson, Inger; Eliasson, Erik; Norsten, C; Ingelman‐Sundberg, Magnus

doi:10.1016/0014-5793(86)80214-9

Cited by 54 publications

(38 citation statements)

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“…The first pathway involves an initial hydroxylation of the methyl group of acetone (and probably also butanone) by a cytochrome P450-type monooxygenase to acetol (1-hydroxyacetone) in mammals (11,12). The second known pathway is initiated by an FADH 2 -and NADPH-dependent monooxygenase in a Gordonia sp., which catalyzes a Bayer-Villiger rearrangement to yield methyl acetic ester (methylacetate) as the first intermediate (13).…”

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confidence: 99%

Acetone and Butanone Metabolism of the Denitrifying Bacterium "Aromatoleum aromaticum" Demonstrates Novel Biochemical Properties of an ATP-Dependent Aliphatic Ketone Carboxylase

Schühle

Heider

2011

Journal of Bacteriology

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The anaerobic and aerobic metabolism of acetone and butanone in the betaproteobacterium "Aromatoleum aromaticum" is initiated by their ATP-dependent carboxylation to acetoacetate and 3-oxopentanoic acid, respectively. Both reactions are catalyzed by the same enzyme, acetone carboxylase, which was purified and characterized. Acetone carboxylase is highly induced under growth on acetone or butanone and accounts for at least 5.5% of total cell protein. The enzyme consists of three subunits of 85, 75, and 20 kDa, respectively, in a (␣␤␥) 2 composition and contains 1 Zn and 2 Fe per heterohexamer but no organic cofactors. Chromatographic analysis of the ATP hydrolysis products indicated that ATP was exclusively cleaved to AMP and 2 P i . The stoichiometry was determined to be 2 ATP consumed per acetone carboxylated. Purified acetone carboxylase from A. aromaticum catalyzes the carboxylation of acetone and butanone as the only substrates. However, the enzyme shows induced (uncoupled) ATPase activity with many other substrates that were not carboxylated. Acetone carboxylase is a member of a protein family that also contains acetone carboxylases of various other organisms, acetophenone carboxylase of A. aromaticum, and ATP-dependent hydantoinases/oxoprolinases. While the members of this family share several characteristic features, they differ with respect to the products of ATP hydrolysis, subunit composition, and metal content.

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Acetone and Butanone Metabolism of the Denitrifying Bacterium "Aromatoleum aromaticum" Demonstrates Novel Biochemical Properties of an ATP-Dependent Aliphatic Ketone Carboxylase

Schühle

Heider

2011

Journal of Bacteriology

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“…Some rats were treated with acetone (5 ml/ kg) intragastrically for two days as described [14]. They received no food, but water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…Treatment of rabbits with acetone, ethanol or imidazole causes the induction of a specific form of liver microsomal cytochrome P-450 which metabolizes aliphatic alcohols [lo -131, acetone [14] and carbon tetrachloride [15]. This form of ethanol-inducible cytochrome P-450 (P-450 LMeb [16], probably identical to isozyme 3a [12]), appears to constitute about 5 -10% of the total cytochrome P-450 in liver microsomes from uninduced animals and 20-40% of the total P-450 in Correspondence to M. Ingelman-Sundberg, Institutionen for Medicinsk Kemi, Karolinska Institutionen, Box 60400, S-10401 Stockholm, Sweden microsomes from induced animals [13, 171.…”

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Metabolism of n-pentane by ethanol-inducible cytochrome P-450 in liver microsomes and reconstituted membranes

Terelius

Ingelman‐Sundberg

1986

Eur J Biochem

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The cytochrome P-450-dependent metabolism of n-pentane was studied by head-space gas chromatographic analysis of incubations with liver microsomes and reconstituted systems from rat and rabbit liver. The alkane was metabolized in liver microsomes from imidazole-treated rabbits at an apparent V,,, of 3 nmol mg-' min-and a K, of 35 pM and in liver microsomes from acetone-treated rats at an apparent V,,, of 10 nmol mg-' min-' and a K, of 9 pM. The rate of microsomal n-pentane metabolism was enhanced fivefold by acetone treatment of rats, compared to the rate observed in liver microsomes from control rats. The reaction was inhibited in microsomes by compounds that are known to interact with the acetone and ethanol-inducible form of liver microsomal cytochrome P-450, like acetone, imidazole, ethanol and benzene. Effective inhibition was also accomplished when microsomal incubations were performed in the presence of IgG against this form of cytochrome P-450 from either rat or rabbit liver. In reconstituted membrane vesicles containing NADPHcytochrome P-450 reductase, ethanol-inducible P-450 from rat liver (P-45Oj) was a fivefold more eficient catalyst of pentane metabolism than was the corresponding P-450 form from rabbit liver (P-450 LMeb). The rabbit enzyme metabolized the hydrocarbon with an apparent V,,, of 4 nmol nmol-' min-' and a K , of 8 pM, By contrast, phenobarbital-inducible P-450 LM2 or 3-methylcholanthrene-inducible P-450 LM4 from rabbit liver were quite ineffective catalysts of n-pentane metabolism. It is concluded that n-pentane constitutes a good substrate for cytochrome P-450 and, in particular, for the ethanol-inducible form of this hemoprotein. It is suggested that npentane is an important substrate for P-450 under in vivo conditions and that pentane measurements in expired air as an indicator of lipid peroxidation must be interpreted with caution.During lipid peroxidation, volatile alkanes like ethane and pentane are formed from polyunsaturated fatty acids [l]. Pentane is formed as the scission product from hydroperoxides of the linoleic acids (cf. [2]). Expired pentane or ethane has been widely used as a sensitive and non-invasive indicator of lipid peroxidation in vivo. However, Frommer et al. [3] showed in 1970 that n-pentane was metabolized by liver microsomes to 2-pentanol preferentially and that cytochrome P-450 probably constituted the catalyst. Recently, several investigators have shown that n-pentane and ethane are metabolized in vivo in rats [4-81, mice [5] and man [9], although the metabolism of ethane is smaller than that of n-pentane. Remmer and coworkers [4, 51 have studied the production of alkanes by liver microsomes and concluded that n-pentane was metabolized in vitro.Treatment of rabbits with acetone, ethanol or imidazole causes the induction of a specific form of liver microsomal cytochrome P-450 which metabolizes aliphatic alcohols [lo -131, acetone [14] and carbon tetrachloride [15]. This form of ethanol-inducible cytochrome P-450 , probably identical to isozyme 3a [12]), ...

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“…CYP2E1 has a key role in gluconeogenesis as the pathway of formation of lactate or glucose from the ketone body acetone is initiated by CYP2E1, and it has been shown that the pathway contributes 5-10% of gluconeogenetic demands (1,2). The pathway is physiologically relevant as acetone levels are highly elevated in Cyp2E1 null mice compared with wild type, during fasting (3).…”

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Lipopolysaccharide Induces CYP2E1 in Astrocytes through MAP Kinase Kinase-3 and C/EBPβ and -δ

Kelicen¹,

Tindberg

2004

Journal of Biological Chemistry

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Cytochrome P450 2E1 (CYP2E1) is highly inducible in a subset of astrocytes in vivo following ischemic or mechanical injury and in vitro by lipopolysaccharide (LPS) or interleukin-1␤. We have studied the mechanism of induction, and found that transcriptional activation of CYP2E1 occurred within 3 h, and CYP2E1 dependent catalytic activity was induced more than 4-fold within 5 h. The induction was sensitive to several tyrosine kinase inhibitors, and was further modulated by inhibitors of p38 MAP kinase. MAP kinase kinase-3 (MKK3) was phosphorylated in response to LPS, and expression of constitutively active MKK3, but not the MAP kinase kinases MEKK1 or MKK1, activated CYP2E1. Transcriptional activation was mediated through a C/EBP␤ and -␦ binding element situated at ؊486/؊474, and appeared to involve activation of prebound factors as well as recruitment of newly synthesized C/EBP␤ and -␦. It is thus suggested that LPS induces MKK3 activation in astrocytes, which in turn stimulates a C/EBP␤ and -␦ binding element to mediate transcriptional activation of CYP2E1.

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Hydroxylation of acetone by ethanol‐ and acetone‐inducible cytochrome P‐450 in liver microsomes and reconstituted membranes

Cited by 54 publications

References 16 publications

Acetone and Butanone Metabolism of the Denitrifying Bacterium "Aromatoleum aromaticum" Demonstrates Novel Biochemical Properties of an ATP-Dependent Aliphatic Ketone Carboxylase

Acetone and Butanone Metabolism of the Denitrifying Bacterium "Aromatoleum aromaticum" Demonstrates Novel Biochemical Properties of an ATP-Dependent Aliphatic Ketone Carboxylase

Metabolism of n-pentane by ethanol-inducible cytochrome P-450 in liver microsomes and reconstituted membranes

Lipopolysaccharide Induces CYP2E1 in Astrocytes through MAP Kinase Kinase-3 and C/EBPβ and -δ

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