Consequences of biotransformation of plant secondary metabolites on acid-base metabolism in mammals—A final common pathway?

Abstract

Regulation of acid-base homeostasis is essential for mammals and birds. Biotransformation and metabolism of absorbed plant secondary metabolites (PSMs) results in the production of organic acids that threaten acid-base homeostasis. Consequently these acids must be buffered and excreted from the body. The production of an acid load from detoxified PSMs should occur in herbivorous mammals and birds and with most PSMs and so may provide a unifying theme to explain many effects of PSMs on animal metabolism. Since the organic acids will be largely ionized at physiological pH, disposal of the hydrogen ion and the organic anion may proceed independently. Most hydrogen ions (H(+)) from organic acids are eliminated by one or more of three ways: (1) when they react with bicarbonate in the extracellular fluid to form carbon dioxide and the carbon dioxide is exhaled, (2) when they bind to dibasic phosphate and are excreted by the kidney as monobasic phosphate, and (3) when they are buffered and retained in the skeletal system. The secretion of phosphate ions and ammonium excretion are two ways in which the kidney replaces bicarbonate ions that have been eliminated as carbon dioxide. Secretion in the kidney tubule is an important means of excreting excessive organic anions rapidly. This process is saturable and may be subject to competition from a variety of different metabolites. Lagomorphs have limited capacity to form new bicarbonate from ammonium excretion and may therefore be obliged to excrete other cations such as sodium to balance the excretion of organic anions from PSMs. Acidemia has wide-ranging impacts on animals but browsing mammals and birds may have to break down muscle tissues to provide for urinary ammonium in order to generate bicarbonate for buffering. Acidemia also can affect the extent of urea recycling. Animals consuming browse diets may have to regulate feeding so that the rate of formation of hydrogen ions does not exceed the rate of disposal. The mechanisms by which this could occur are unknown.

Preference by sheep for endophyte-infected tall fescue grown adjacent to or at a distance from alfalfa

“…often with nitrogenous compounds such as glycine or glucuronic acid, and excretion of detoxified products (Foley et al, 1995;Illius and Jessop, 1995). Nitrogen is lost through increased ammonium excretion, which buffers high acid loads from compounds such as glucuronic acid (Foley et al, 1995).…”

Functional and energetic characterization of P-gp-mediated doxorubicin transport in rainbow trout (Oncorhynchus mykiss) hepatocytes

“…Such costs may include those associated with biotransformation and excretion Kenndy 2004, 2005), maintenance of acid-base balance altered by the production of acidic metabolites (Foley, 1992(Foley, , 1995, active efflux of xenobiotics by ATP-dependent drug efflux pumps such as P-gp (Bains and Kenndey, 2005), as well as long-term costs associated with physical alterations of the tissues or organs involved in detoxification (Hinton and Lauren 1990;Rubin and Lieber 1974).…”

“…The production of large acid loads through biotransformation and metabolism of compounds can threaten acid-base homeostasis, and there is evidence that there are costs in dealing with large acid loads produced from the biotransformation and metabolism of xenobiotics such as plant secondary metabolites (PSM) (Foley, 1992(Foley, , 1995.…”

“…Disturbances of acid-base balance show wide-ranging effects on biochemical and physiological processes of animals including effects on organ systems (respiratory, cardiovascular, and skeletal), whole body homeostasis, and metabolism of carbohydrates, proteins and nitrogen (Foley, 1995). Organic acids are dealt with by being buffered and removed from the body which is sl,.lggested to be energetically costly to an organism (Foley, 1992).…”

Journal of Range Management, Volume 55, Number 3 (May 2002)

“…Acceptability within the foraging milieu is influenced greatly by an animal's past experiences such as social and environmental interactions (Provenza et al 1992(Provenza et al , 1993 (Strydom and Joubert 1983, Kellerman 1987, Fredrickson et al 2000. Animals are also more likely to eat familiar, toxic plants in unfamiliar settings (Burritt and Provenza 1997 (Freeland and Janzen 1974, Foley et al 1995, Illius and Jessop 1995. Naive animals initially exposed to some toxic plants may be more vulnerable because of reduced detoxification abilities either from a lack of adapted rumen microbes (Duncan et al 2000) or a lack of inducible enzyme systems (Galtier 1999).…”