Inhibition of long-chain fatty acid oxidation by methylglyoxal bis(guanylhydrazone).

Methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of spermidine and spermine biosynthesis and clinically used anti-cancer drug, powerfully inhibited carnitine-dependent fatty acid oxidation in heart muscle homogenates. Equipotent inhibition was also produced by spermine whereas spermidine and putrescine were less effective. MGBG appeared to act as a competitive inhibitor in respect to carnitine. Even though MGBG and spermine equally effectively depressed palmitate oxidation in muscle homogenates in vitro, a striking difference existed between the compounds as regards their effects on fatty acid oxidation in cultured tumor cells. Micromolar concentrations of MGBG distinctly impaired palmitate utilization also in cultured L 1210 leukemia cells, whereas similar concentrations of spermine markedly enhanced the oxidation of the fatty acid. The inhibitory effect of MGBG in cultured tumor cells was, at least partly, reversed upon addition of exogenous carnitine. The finding indicating that MGBG impairs fatty acid utilization may be an explanation for the known hypoglycemic effect produced by the drug in most animal species as well as for some of the side-effects associated with its clinical use, most notably severe myalgia.