The effect of hexachlorophene and related compounds on torula yeast glucose-6-phosphate dehydrogenase and some other dehydrogenase enzymes Public Deposited

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  • Low concentrations of hexachlorophene (HCP) inhibit a number of pyridine nucleotide-linked dehydrogenase enzymes. The I₅₀ HCP concentrations were 105 μM for pig heart isocitrate dehydrogenase (ICD), 65 μM for horse liver alcohol dehydrogenase, 39 μM for torula yeast glucose-6-phosphate dehydrogenase (G6PD), 6.0 μM for beef heart malate dehydrogenase, and 1.6 μM for bovine liver glutamate dehydrogenase (GDH) at the enzyme concentrations tested. HCP exhibited cooperative inhibition of these enzymes since the observed maximum interaction coefficient, n', between HCP binding sites ranged between 1.62 and 3.33 but it was not an allosteric effector as evidenced by Hill coefficients for the substrates of approximately 1.0 both in the absence and the presence of HCP. More detailed kinetic analysis showed that HCP in most cases exhibited mixed kinetics, giving average K[subscript i] values with G6PD of 16.6 μM for NADP⁺ and 18.2 μM for glucose -6- phosphate; with ICD of 171 µM for NADP⁺ and 4.0 μM for isocitrate; and with GDH of 0.7 μM for NADH, 1.4 μM for a-ketoglutarate and 0.5 µM for ammonium acetate, under the conditions studied. The kinetics of inhibition of torula yeast G6PD by other bisphenols, 3,4-TCP and DCP, were similar to those found with HCP. Kinetic analysis suggested that inhibition of G6PD, ICD, and GDH by HCP probably involved binding of the bisphenol to at least two inhibitory sites. The effect of HCP on torula yeast G6PD was studied further by the methods of density gradient ultracentrifugation, equilibrium dialysis, acrylamide electrophoresis, and difference spectroscopy. The results from these studies suggest that the mechamism for inhibition of dehydrogenases by HCP and related compounds is quite complex, probably involving, at least in the case of torula yeast G6PD: the direct binding of HCP to the enzyme, resulting in inhibition and conformational changes in the enzyme and dissociation of the active dimeric form of the enzyme to its inactive subunits. In some cases the binding of HCP to G6PD not only caused dissociation, but also resulted in the formation of aggregates of higher molecular weight as observed by density gradient ultracentrifugation and electrophoresis. Maximum binding of 52 moles of HCP to each mole of G6PD was found but saturation was not reached even at the highest HCP concentrations that could be tested. While probably not an important mechanism for inhibition, some evidence was obtained suggesting that HCP formed complexes with the G6PD substrates, NADP⁺ and G6P.
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