206
RACHMIEL LEVINE
most normal mammalian tissues the rate of oxygen consumption is rigidly
controlled and kept well below the capacity of the tissue supply of the
catalytic systems. "Need," in the form of energy used, brings with it
a concommitant rise in respiration. This is best exemplified in muscle,
which increases its rate of oxygen consumption in accordance with the
degree of work being performed. A great deal of evidence exists to show
that this correlative control is exerted somewhat as follows: muscular
contraction, i.e., actomyosin shortening, is associated with the breakdown
of ATP (adenosine triphosphate) to ADP (adenosine diphosphate).
An increase in the rate and degree of contraction leads therefore to an
increased rate of ATP breakdown and an increased rate of supply of
ADP. Reconstitution of ATP occurs by raising inorganic Ρ to the energy
level of ATP by means of energy yielded by an oxidative or dehydrogenating step in the intermediary metabolic scheme. Many oxidative
steps are thus "coupled" with the formation of high-energy phosphate
groups. To a large extent these oxidative rates are dependent upon the
availability of phosphate acceptors (e.g., ADP) and the rate of use
of the energy determines the amount of such acceptors ready to become
rephosphorylated. Conversely, if all the ADP has been transformed to
ATP, none would be available for the coupling, and the oxidative reactions become slowed down. One way, then, of raising the rate of oxygen
consumption is to draw off the energy stored in high-energy bonds in
the form of work (mechanical, electrical, chemical, etc.). In many
tissues there exists an enzyme ATPase which splits ATP, probably
hydrolytically, and the energy is liberated directly as heat. An activation
of such an enzyme would pull the oxidative reactions at a faster pace. A
third possibility is that the coupling between oxidation and phosphorylation is disrupted and the oxidative rate ceases to be controlled, and is now
no longer dependent upon the ADP/ATP ratio. Many substances have
been shown to uncouple the P/O relationship, notably dinitrophenol;
and it is thought that its calorigenic effect is due to its action in lowering the P/O ratio. In recent years workers in several laboratories have
attempted to determine whether the effect of thyroid on cell respiration
is exerted by an uncoupling at one or more of the steps in the oxidative
chain of reactions (Lardy and Feldott, 1951; Lardy and Wellman, 1952;
Martius and Hess, 1955; Martius et al., 1955; Dutoit, 1952; Lipmann and
Dutoit, 1951; Mudd et al, 1955).
There is no doubt that thyroxine and triiodothyronine can be shown
to have an effect both in vivo and in vitro on the P/O ratio. With the
higher amounts of the hormone the P/O ratio is markedly depressed in
liver slices taken from hyperthyroid animals and in "normal" mitochondria preincubated with the active substances. Lower concentrations
RACHMIEL LEVINE
most normal mammalian tissues the rate of oxygen consumption is rigidly
controlled and kept well below the capacity of the tissue supply of the
catalytic systems. "Need," in the form of energy used, brings with it
a concommitant rise in respiration. This is best exemplified in muscle,
which increases its rate of oxygen consumption in accordance with the
degree of work being performed. A great deal of evidence exists to show
that this correlative control is exerted somewhat as follows: muscular
contraction, i.e., actomyosin shortening, is associated with the breakdown
of ATP (adenosine triphosphate) to ADP (adenosine diphosphate).
An increase in the rate and degree of contraction leads therefore to an
increased rate of ATP breakdown and an increased rate of supply of
ADP. Reconstitution of ATP occurs by raising inorganic Ρ to the energy
level of ATP by means of energy yielded by an oxidative or dehydrogenating step in the intermediary metabolic scheme. Many oxidative
steps are thus "coupled" with the formation of high-energy phosphate
groups. To a large extent these oxidative rates are dependent upon the
availability of phosphate acceptors (e.g., ADP) and the rate of use
of the energy determines the amount of such acceptors ready to become
rephosphorylated. Conversely, if all the ADP has been transformed to
ATP, none would be available for the coupling, and the oxidative reactions become slowed down. One way, then, of raising the rate of oxygen
consumption is to draw off the energy stored in high-energy bonds in
the form of work (mechanical, electrical, chemical, etc.). In many
tissues there exists an enzyme ATPase which splits ATP, probably
hydrolytically, and the energy is liberated directly as heat. An activation
of such an enzyme would pull the oxidative reactions at a faster pace. A
third possibility is that the coupling between oxidation and phosphorylation is disrupted and the oxidative rate ceases to be controlled, and is now
no longer dependent upon the ADP/ATP ratio. Many substances have
been shown to uncouple the P/O relationship, notably dinitrophenol;
and it is thought that its calorigenic effect is due to its action in lowering the P/O ratio. In recent years workers in several laboratories have
attempted to determine whether the effect of thyroid on cell respiration
is exerted by an uncoupling at one or more of the steps in the oxidative
chain of reactions (Lardy and Feldott, 1951; Lardy and Wellman, 1952;
Martius and Hess, 1955; Martius et al., 1955; Dutoit, 1952; Lipmann and
Dutoit, 1951; Mudd et al, 1955).
There is no doubt that thyroxine and triiodothyronine can be shown
to have an effect both in vivo and in vitro on the P/O ratio. With the
higher amounts of the hormone the P/O ratio is markedly depressed in
liver slices taken from hyperthyroid animals and in "normal" mitochondria preincubated with the active substances. Lower concentrations