Activation of promutagens by liver homogenates isolated from female mice at different ages; lack of significant differences.

Liver S-9 (9000 g supernatant) fractions isolated from 2-, 12- and 26-month untreated female Swiss-Webster mice were compared under different assay conditions as to their abilities to activate 2-acetylaminofluorene, benzo(a)pyrene, and dimethylnitrosamine to mutagens in Salmonella typhimurium tester strain TA 100. All fractions activated these compounds to mutagens, although 2-acetylaminofluorene was only weakly mutagenic. Some differences in the activating abilities of the three age groups were observed but they were for the most part relatively small.

Serotonin and its precursors as modulators of the immunological responsiveness in mice.

Central nervous system regulation of endocrine functions is mediated by neurotransmitters, via hypothalamic hypophysiotropic factors which in turn control anterior pituitary functions. The evidence of serotonergic-endocrine interrelations with regard to adrenal, thyroid, gonadal and prolactin functions is fast accumulating. Our study extends the importance of those interrelations to some functions of the immune system. Multiple administration of 5-hydroxytryptamine(serotonin) or its precursor, 5-hydroxy-L-tryptophan(5-HTPH), produces marked depression of T cell dependent, humoral, hemolytic, primary immune response in mice. L-tryptophan, a more distant serotonin precursor, produces slight but significant depression of this immune response. Multiple treatment of mice infected with Friend Leukemia Virus (FLV) with serotonin or 5-HTPH alone or in combination with cyclophosphamide (Cytoxan) results in significant delay of the clinical progression of the infection. L-tryptophan produces a modest but significant improvement. Administration of serotonin or 5-HTPH causes a marked reduction of the thymus weight. It is reasonable to postulate that the described effects result from the thymus involution which affects the T cell compartment of the immune system. This is the consequence of hormonal imbalance caused by the alteration of the serotonin biosynthetic pathway in the brain. The adrenal cortex is not implicated in the mediation of this effect. Since many clinically used drugs affect the serotonin metabolism, the clinical consequences of the resulting alteration of the immunological responsiveness should be considered.

Immunological senescence in mice and its reversal by coenzyme Q10.

A pronounced suppression of the humoral, hemolytic, primary immune response in old (22 months) mice was demonstrated as compared with this response in young (10 weeks) mice. The suppression is associated with a lower thymus weight:body weight ratio. In contrast, the ratios spleen weight:body weight and liver weight:body weight in 10 weeks and 22 months old mice remain almost constant. A single administration of coenzyme Q10--a non-toxic, non-specific stimulant of the host defense system--partly compensates the age-determined suppression of the humoral, immune response. This suppression probably results from an age-dependent imbalance of T cells: B cells ratio and a decline of their immunological responsiveness which is compensated by the administration of coenzyme Q10.

Coenzyme Q deficiency in aged mice.

The specific activities of the succinate dehydrogenase-coenzyme Q reductase were determined in mitochondria from the thymus and the spleen of aged mice (20, 22 and 24 months) as compared with young mice (10 weeks). Significant steep escalation of the deficiency of coenzyme Q-enzyme activity was observed in the thymus of all three groups of aged mice. No significant deficiency was found in the mitochondria of the spleen. The ratios between the liver weight:body weight and the spleen weight:body weight in young and aged mice are practically unchanged, but the thymus weight:body weight ratio decreases significantly in all three groups of aged mice. The described age-dependent anatomical and functional alterations in the thymus most likely form the base for the development of the T cell determined suppression of the immunological responsiveness, present in aged mice.

Immunostimulation or immunodepression?

Our experimental studies and extensive literature survey established that the overall response of an experimentally modified host defense system is strongly dose-dependent, irrespective of either the modifying agent or the test model system. If a sufficiently broad dose range is used, an irregular, nonlinear, nonmonotonic response curve is formed, generally W- or M-shaped, depending on the parameters selected for the representation, with two peaks of relative maximal effect. Accordingly, a modifying agent may exhibit, in some cases, dual effect--stimulation and depression, each at different dose levels. This typical response is defined as characteristic of the entire host defense system and therefore implies a biologically integrated system. The described dose-response relationship mandates the use of multiple doses in evaluation experiments, to establish efficacy and especially to design optimal dose schedules for experimental and clinical application of any agent modifying the host defense system activity.

Coenzyme Q deficiency in mice following infection with Friend leukemia virus.

The specific activities of the succinate dehydrogenase-coenzyme Q reductase were assayed on mitochondrial preparations of this enzyme from spleen, liver, blood and peritoneal macrophages of mice infected with Friend leukemia virus, and of control mice. Significant increases in the deficiency of coenzyme Q-enzyme activity were found in the spleen and blood of infected animals as the infection progressed. No significant deficiency was observed in the liver or the peritoneal macrophages. The development of the deficiency and splenomegaly during infection seemingly correlate with previous data which showed that administration of coenzyme Q resulted in a reversal of splenomegaly and a reduction in mortality. A limiting factor in the resistance of mice to Friend leukemia virus appears to be the availability of coenzyme Q.

Effect of stimulation of the host defense system by coenzyme Q 10 on dibenzpyrene-induced tumors and infection with Friend leukemia virus in mice.

Members of the coenzyme Q group increase the phagocytic activity in rats, as measured by the carbon clearance technique, and increase the hemolytic antibody formation in mice. In addition, prior treatment with low doses of chloroquine hydrochloride combined with coenzyme Q(10) results in increased numbers of survivors, prolonged survival time, and reduced parasitemia in blood-transferred Plasmodium berghei infection in miceIn an extension of these studies, using emulsions of coenzyme Q(10), I demonstrated the following effects on two tumor systems in mice: (i) Treatment with coenzyme Q(10) decreased splenomegaly and hepatomegaly and increased the number of surviving mice infected with Friend leukemia virus. (ii) Treatment with coenzyme Q(10) reduced the percentage of mice with tumors, increased the number of survivors, and reduced the tumor size in mice with tumors induced by 3,4,9,10-dibenzpyrene. The effect on both tumor systems was dose-dependent. These studies support the hypothesis that the host defense system plays a definitive role in the defense of the host against invasion by various agents, including neoplasia.