MECHANISMS OF HORMONE ACTIONS
207
of the hormones may however not depress the P/O ratio, and under
certain conditions the mitochondrial capacity for phosphate esterification
may even be better preserved than without thyroxine. Livers of thyroidectomized animals have a lessened capacity to incorporate aminoacids, which is restored by thyroid substitution therapy, an action which
is consistent with better utilization of generated energy rather than with
a depression of phosphorylation.
When one analyzes the metabolic behavior of hypothyroid, euthyroid,
and hyperthyroid animals in vivo, and attempts to correlate it with the
notion that the hormone acts initially to depress the P/O ratio one meets
with many inconsistencies. However, severe hyperthyroidism, experimental or clinical, is associated with an uncontrolled, inefficient use of
energy. This suggests that the "physiological" action of the thyroid
hormones is not one of uncoupling phosphorylation from oxidation. Uncoupling would be the expression of a "pharmacological" action of unphysiological amounts of thyroxine. Oxidative phosphorylation seems
to be sensitive to many and varied conditions and chemical substances,
wholly unrelated to thyroid action (Brody, 1955). Uncoupling by
thyroxine in vitro can be prevented or reversed by magnesium (Mudd
et al, 1955); an observation which finds a counterpart in the previous
demonstration that in thyroid disease the blood magnesium levels are
disturbed (Soffer et al, 1941).
The most recent work from Lehninger's laboratory (Lehninger and
Gaebler, 1956) is beginning to provide us with more insight into the
control of mitochondrial respiration, and the manner by which ions,
drugs, and hormones may affect it. Agents which "uncouple" respiration
from phosphate uptake differ as to their mechanisms of action. Dinitrophenol and Dicumarol, for example, will "uncouple" the oxidative phosphorylation of whole mitochondria; and these drugs will also act on
the isolated multienzyme preparation obtained from mitochondria. The
isolated system does not possess a membrane. The thyroid active compounds (thyroxine, triiodothyronine) and Ca
++ will lead to "uncoupling"
only when unbroken mitochondria are used. At the same time thyroxine
and Ca
++
also cause "swelling" of mitochondria, most probably by an
action on the mitochondrial membrane. The "swelling" action can be
obtained with concentrations of thyroxine which do not lead to "uncoupling."
It would seem that the action of thyroxine may be more directly related to membrane permeability for electrolytes and water, than to the
enzymes of respiration.
207
of the hormones may however not depress the P/O ratio, and under
certain conditions the mitochondrial capacity for phosphate esterification
may even be better preserved than without thyroxine. Livers of thyroidectomized animals have a lessened capacity to incorporate aminoacids, which is restored by thyroid substitution therapy, an action which
is consistent with better utilization of generated energy rather than with
a depression of phosphorylation.
When one analyzes the metabolic behavior of hypothyroid, euthyroid,
and hyperthyroid animals in vivo, and attempts to correlate it with the
notion that the hormone acts initially to depress the P/O ratio one meets
with many inconsistencies. However, severe hyperthyroidism, experimental or clinical, is associated with an uncontrolled, inefficient use of
energy. This suggests that the "physiological" action of the thyroid
hormones is not one of uncoupling phosphorylation from oxidation. Uncoupling would be the expression of a "pharmacological" action of unphysiological amounts of thyroxine. Oxidative phosphorylation seems
to be sensitive to many and varied conditions and chemical substances,
wholly unrelated to thyroid action (Brody, 1955). Uncoupling by
thyroxine in vitro can be prevented or reversed by magnesium (Mudd
et al, 1955); an observation which finds a counterpart in the previous
demonstration that in thyroid disease the blood magnesium levels are
disturbed (Soffer et al, 1941).
The most recent work from Lehninger's laboratory (Lehninger and
Gaebler, 1956) is beginning to provide us with more insight into the
control of mitochondrial respiration, and the manner by which ions,
drugs, and hormones may affect it. Agents which "uncouple" respiration
from phosphate uptake differ as to their mechanisms of action. Dinitrophenol and Dicumarol, for example, will "uncouple" the oxidative phosphorylation of whole mitochondria; and these drugs will also act on
the isolated multienzyme preparation obtained from mitochondria. The
isolated system does not possess a membrane. The thyroid active compounds (thyroxine, triiodothyronine) and Ca
++ will lead to "uncoupling"
only when unbroken mitochondria are used. At the same time thyroxine
and Ca
++
also cause "swelling" of mitochondria, most probably by an
action on the mitochondrial membrane. The "swelling" action can be
obtained with concentrations of thyroxine which do not lead to "uncoupling."
It would seem that the action of thyroxine may be more directly related to membrane permeability for electrolytes and water, than to the
enzymes of respiration.