Is Cimetidine a VitaleTheine Analogue?

Cimetidine, a H-2 type anti-histamine, has been used to treat horses with melanoma with controversial results. Although better results have been reported in mouse models, and there are some indications of efficacy in humans with melanoma, cimetidine is generally considered to be palliative in cancer treatment. Responses to xenobiotic drugs often are not predictable from one species to the next due to species differences in drug metabolizing enzymes. However, it is encouraging so far that extrapolation of therapeutic responses between species does not appear to be a problem with low concentrations of the vitaletheine modulators, a result that would be expected if the vitaletheine modulators are constitutive in normal mammalian tissues.

Differences between cimetidine (Tagamet ® SmithKline Beecham) and vitaletheine are numerous, but the cysteamine moiety of vitaletheine (below left) is present in cimetidine as an alkyl sulfide (below center) and the nucleophilic nitrogens (dark blue) of cimetidine are positioned at locations similar to those nucleophilic nitrogens and oxygens (red) of vitaletheine. Cimetidine also bears some resemblance to ß-alethine (below right) suggesting anti-histamine (antacid) potential for the vitaletheine modulators and related compounds.

Despite structural differences, Cimetidine and a related H-2 receptor antagonist, ranitidine (Zantac® Glaxo, Inc.), are still substrates for the FAD-containing monooxygenase, but slow turnovers (low Vmax) on the enzyme make undesirable inhibition of other monooxygenase-catalyzed reactions by these H-2 blockers likely. This concern is justified further by the observation that immunological responses to cimetidine appear to be mediated through suppressor and helper T-lymphocytes and natural killer cells which differs from TH-2 type of immune modulation produced by the vitaletheine modulators.

In contrast to vitalethine's efficacy in treating cancer it is also interesting that many of the H-1 type anti-histamines now on the market, like substrates for the monooxygenase bearing little resemblance to vitaletheine, increase the growth of tumors in rodents. The observed uncoupling of the down-regulation of HMG-CoA reductase by n-octylamine, an amine approximately the same size as histamine, may provide a mechanism for tumor stimulation by these types of compounds.
Cimetidine
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