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This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glycoproteins, defective membrane formation and structure and reduced lysosomal stability leading to disordered contact inhibition and tumour antigen presentation contributing to oncogenesis. Digoxin induced alteration in intracellular calcium/magnesium ratios and low ubiquinone levels can lead to a mitochondrial dysfunction resulting in increased free radical generation and reduced scavenging & caspase-3 activation producing a P21 defect contributing to oncogenesis.

Objectives: Hypothalamic digoxin, an isoprenoidal metabolite, is an endogenous regulator of membrane Na(+)-K(+) ATPase activity, immune activation and synaptic neurotransmission. The objective of this study was to assess the role of hypothalamic digoxin and hemispheric dominance in the pathogenesis of the acquired immunodeficiency syndrome (AIDS) and in the genesis of sexual orientation., Methods: The isoprenoid-pathway-related cascade - (i) isoprenoidal metabolites - digoxin, dolichol and ubiquinone, (ii) tryptophan/tyrosine catabolic patterns, (iii) glycoconjugate metabolism, (iv) free radical metabolism and (v) membrane composition were assessed in AIDS (CDC stage - group IV - subgroup C), individuals with differing hemispheric dominance as well as in individuals with differing sexual orientation. Statistical analysis was done by Student's t test with modified degrees of freedom., Results: The HMG CoA reductase activity was increased with increased digoxin and dolichol levels and reduced ubiquinone levels in AIDS. The membrane Na(+)-K(+) ATPase activity and serum magnesium levels were reduced. The tryptophan catabolites (serotonin, quinolinic acid, nicotine and strychnine) were increased and the tyrosine catabolites (morphine, dopamine and noradrenaline) were reduced. The serum glycoconjugate metabolites were increased and lysosomal stability was reduced in AIDS. There was reduced incorporation of glycoconjugates into membranes and an increased membrane cholesterol:phospholipid ratio. Lipid peroxidation products and NO were increased while free radical scavenging enzymes and reduced glutathione were reduced. The biochemical patterns obtained in AIDS correlated with those obtained in right-hemispheric dominance and homosexuals/bisexual states., Conclusions: Hypothalamic digoxin and right-hemispheric dominance is important in the predisposition to AIDS as well as homosexual/bisexual states., (Copyright 2002 S. Karger AG, Basel)