Review
On the mammalian acetone metabolism: from chemistry to clinical implications

https://doi.org/10.1016/S0304-4165(03)00051-5Get rights and content

Abstract

Despite the description of the ways of acetone metabolism, its real role(s) is (are) still unknown in metabolic network. In this article, a trial is made to ascertain a comprehensive overview of acetone research extending discussion from chemistry to clinical implications. Mammals are quite similar regarding their acetone metabolism, even if species differences can also be observed. By reviewing experimental data, it seems that plasma concentration of acetone in different species is in the order of 10 μm range and the concentration-dependent acetone metabolism is common to all mammals. At low concentrations of plasma acetone, the C3 pathways are operative, while at higher concentrations, the metabolism through acetate becomes dominant. Glucose formation from acetone may also contribute to the maintenance of a constant blood glucose level, but it seems to be only a minor source for that. From energetical point of view, an interorgan cooperation is suggested because transportable C3 fragments produced in the liver can serve as alternative sources of energy for the peripheral tissues in the short of circulating glucose. The degradation of acetoacetate to acetone contributes to the maintenance of pH buffering capacity, as well. Special attention is paid to the discussion of acetone production in diseases amongst which endogenous and exogenous acetonemiae have been defined. Acetonemiae of endogenous origin are due to the increased rate of acetone production followed by an increase of degrading capacity as cytochrome P450IIE1 (CYPIIE1) isozymes become induced. Exogenous acetonemiae usually resulted from intoxications caused by either acetone itself or other exogenous compounds (ethanol, isopropyl alcohol). It is highlighted that, on the one hand, isopropanol is also a normal constituent of metabolism and, on the other hand, the flat opinion that the elevation of its plasma level is a sign of alcoholism cannot further be held. The possible future directions of research upon acetone are depicted by emphasizing the need for the clear-cut identification of mammalian acetoacetate decarboxylase, and the investigation of race differences and genetic background of acetone metabolism.

Introduction

Most probably the presence of acetone in scientific thinking may be dated from 1798, when an English physician, John Gallo, described a material in human breath of an odor of decaying apples [1]. In 1857, this compound was identified as acetone [1]. At that time, acetone was regarded as a characteristic feature of diabetic coma [1]. By the end of nineteenth century, on the basis of the observations of Schwartz [2] made in dogs and of Geelmuyden [3] made in rabbits, dogs and humans, it was concluded that acetone was not a worth-mentioning intermediate of metabolism. The above findings were corroborated by the experiments of Koehler et al., who after having reinvestigated the fate of acetone in humans came to the same conclusion, namely, acetone was poorly, if at all, utilized [4].

For a long time, acetone was regarded as a waste product of metabolism. This flat opinion on its role in metabolism started changing in the second third of twentieth century, when radioactive compounds were initiated in biochemical research. Since the end of 1940s, experimental data became available showing that 14C-carbons of labelled acetone were found in cholesterol, fatty acids, urea and glycogen, thus opposing the dogma that mammals were unable to metabolize acetone to intermediates of metabolism in a substantial degree [5], [6], [7], [8], [9]. Extensive oxidation of acetone to carbon dioxide exhaled in respiratory air was also recognized [6], [9], [10]. The possibility of in vivo formation of glucose from acetone in experimental animals was also published by several groups [9], [10], [11], [12], [13], [14], [15]. In vitro glucose formation from acetone was detected in isolated rat and murine hepatocytes [16], [17], but not in perfused rat liver [18]. Accordingly, 2-14C-acetone was reported to incorporate into glucose in fasting and diabetic humans [19], [20].

In the mid-1980s, two papers appeared trying to give an overview of the metabolic pathways of acetone metabolism [21], [22]. At that time, acetone research was brought into the focus and lived its second golden age, but since the 1990s, the interest has shown a tendency to decrease. This trend becomes obvious if somebody takes into consideration the number of papers published in this field. This paper reviews the chemistry of acetone in brief, the studies of acetone metabolism mostly in mammals, both in vivo and in vitro, and the toxicity of acetone. Attention is also paid to the possible physiological roles of acetone metabolism in humans and to the roles of acetone in disease processes.

Section snippets

Chemistry of acetone

Acetone (2-propanone, dimethyl ketone, β-keto-propane, pyroacetic ether) is a volatile, highly flammable liquid with a characteristic odor.

Acetone metabolism in mammals

At the end of nineteenth century, it was Schwartz, who demonstrated that less portion of administered acetone was recovered in the breath of dogs when the dose was lowered, thus raising the possibility of acetone metabolism at a very low rate if added in a small amount [2]. Later extensive studies were undertaken mostly with rats.

After administration of 2-14C-acetone or 1, 3-14C-acetone to rats by stomach tube or by injection, the examination of animal carcasses led to a demonstrable amount of

Acetone metabolism in vitro

Using liver homogenates, Rudney [46] and Coleman [44] detected 1,2-propanediol and lactate formation from 2-14C-acetone, respectively. In contrast, the first papers upon its in vitro metabolism in rat liver slices led to the conclusion that liver was able to convert acetone into metabolically active C2 fragments finally resulting in acetate formation [5], [8].

Casazza et al. [16] prepared hepatocytes from male rats maintained on 1% acetone drinking water for 5–6 days and starved for 48 h before

Production of acetone

There are two sources of acetone production: the decarboxylation of acetoacetate and the dehydrogenation of isopropanol. The former compound seems to be the major source of acetone in mammals and arises from either lipolysis or amino acid degradation.

Clinical implications

For etiological reasons, acetonemiae are classified as of endogenous and exogenous origin. An acetonemia is referred to as endogenous when the reason of why plasma level of acetone increases is due to a metabolic disturbance related to a disease or to physical exercise (Table 2). In all other cases, acetonemia is considered of exogenous origin regardless of whether the cause of the rise of plasma acetone concentration is the intake of an acetone precursor (e.g. isopropanol) or acetone itself,

Conclusions

Even in 1980, Robinson and Williamson [163] wrote in their work on ketone bodies, that “we make no mention of acetone, which is formed by non-enzymatic breakdown of acetoacetate and is unlikely to be important in metabolism of the intact animal”. Since then, lots happened in this field and in present days, it is beyond doubt that acetone is a normal constituent of metabolism and cannot be regarded as a waste product of metabolism [21], [22]. However, there are two sets of problems that we face.

Acknowledgements

At that time when the experiments were undertaken by the author and his coworkers, the financial support was provided by the Ministry of Welfare (Budapest, Hungary). Herewith, the author acknowledges Ms. Gizella Ferencz, Ms. Anikó Lakatos, Mr. Tamás Gábler and Mr. Antal Holly for their participation in the technical part of the experiments. Dr. Gábor Bánhegyi, Dr. Ferenc Antoni, Tamás Garzó, Dr. József Mandl and Dr. Pál Riba are acknowledged for their valuable participation in discussions when

References (173)

  • A.E. Koehler et al.

    J. Biol. Chem.

    (1941)
  • E. Borek et al.

    J. Biol. Chem.

    (1949)
  • W. Sakami

    J. Biol. Chem.

    (1950)
  • R.O. Brady et al.

    J. Biol. Chem.

    (1951)
  • K. Kosugi et al.

    J. Biol. Chem.

    (1986)
  • K. Kosugi et al.

    J. Biol. Chem.

    (1986)
  • J.P. Casazza et al.

    J. Biol. Chem.

    (1984)
  • M.P. Kalapos et al.

    Int. J. Biochem.

    (1994)
  • V.C. Gavino et al.

    J. Biol. Chem.

    (1987)
  • J.M. Argiles

    Trends Biochem. Sci.

    (1986)
  • B.R. Landau et al.

    Trends Biochem. Sci.

    (1987)
  • I. Zabin et al.

    J. Biol. Chem.

    (1950)
  • J.A. Behre

    J. Biol. Chem.

    (1940)
  • L.A. Greenberg et al.

    J. Biol. Chem.

    (1944)
  • G. Rooth et al.

    Lancet ii

    (1966)
  • J. Peinado et al.

    J. Chromatogr.

    (1987)
  • T. Mitsui et al.

    Clin. Chim. Acta

    (1999)
  • F.Y. Bondoc et al.

    Biochem. Pharmacol.

    (1999)
  • A. Brega et al.

    J. Chromatogr.

    (1991)
  • J.P. Casazza et al.

    Arch. Biochem. Biophys.

    (1994)
  • J.P. Casazza et al.

    Anal. Biochem.

    (1985)
  • H. Rudney

    J. Biol. Chem.

    (1954)
  • Y. Sugawa-Katayama et al.

    J. Nutr.

    (1975)
  • M.P. Kalapos et al.

    Int. J. Biochem. Cell Biol.

    (1996)
  • G. van Stekelenburg et al.

    Clin. Chim. Acta

    (1972)
  • G. Koorevaar et al.

    Clin. Chim. Acta

    (1976)
  • R. Nordmann et al.

    Life Sci.

    (1973)
  • D.R. Koop et al.

    J. Biol. Chem.

    (1985)
  • R. Kato et al.

    Jpn. J. Pharmacol.

    (1970)
  • F.M. Farin et al.

    Toxicol. Appl. Pharmacol.

    (1994)
  • S.C. Khani et al.

    J. Biol. Chem.

    (1988)
  • U. Subramanian et al.

    Toxicol. Appl. Pharmacol.

    (1995)
  • M. Tsutsumi et al.

    Int. Hepatol. Commun.

    (1994)
  • M. Ingelman-Sundberg et al.

    Biochem. Biophys. Res. Commun.

    (1988)
  • J.J. Hu et al.

    Biochem. Pharmacol.

    (1990)
  • H. Rudney

    J. Biol. Chem.

    (1954)
  • M.P. Kalapos

    Med. Hypotheses

    (1999)
  • M.P. Kalapos et al.

    Biochim. Biophys. Acta

    (1991)
  • O.B. Crofford et al.

    Trans. Am. Clin. Climatol. Assoc.

    (1977)
  • L. Schwartz

    Arch. Exp. Pathol. Pharmakol.

    (1898)
  • H.C. Geelmuyden

    Z. Physiol. Chem.

    (1897)
  • D. Price et al.

    J. Biol. Chem.

    (1950)
  • G.A. Mourkides et al.

    J. Biol. Chem.

    (1958)
  • E.N. Bergman et al.

    Am. J. Physiol.

    (1960)
  • A.L. Black et al.

    Am. J. Physiol.

    (1972)
  • G. Hetényi et al.

    Biochem. J.

    (1985)
  • G. Hetényi et al.

    Horm. Metab. Res.

    (1987)
  • O.E. Owen et al.

    Diabetes

    (1982)
  • G.A. Reichard et al.

    J. Clin. Invest.

    (1979)
  • J.M. Weiss

    Chem. Eng. News

    (1958)
  • Cited by (176)

    • Profiling of exhaled volatile organics in the screening scenario of a COVID-19 test center

      2022, iScience
      Citation Excerpt :

      As SARS-CoV-2 infection causes dysbiosis of intestinal flora and disrupts gut barrier integrity leading toward leaky gut (Giron et al., 2021; Hussain et al., 2021), it is likely to reduce upstream production of crotonaldehyde but to increase uptake of glucose. Consequently, the exhalation of the putative biproduct of hepatic and cellular glycolysis, i.e. acetone (Kalapos, 2003), increased significantly in the SARS-CoV-2-infected individuals, while compared to the healthy subjects. In line with our findings, elevated breath acetone concentrations in COVID-19 patients are also reported in a recent study (Ruszkiewicz et al., 2020).

    • Flame-made chemoresistive gas sensors and devices

      2022, Progress in Energy and Combustion Science
    View all citing articles on Scopus
    View full text