Cholesterol Biosynthesis from Lanosterol: Differential Inhibition of Sterol Δ⁸-Isomerase and Other Lanosterol-Converting Enzymes by Tamoxifen

The fact that administration of tamoxifen (Tam) to humans and laboratory animals (e.g., rats and monkeys) results in both a drastic reduction in cholesterol and a marked accumulation of certain sterol intermediates in their serum led us to undertake more direct biochemical studies on the mechanism of Tam's inhibitory action on the cholesterogenic enzymes. Of the five rat hepatic lanosterol-converting enzymes examined, the enzyme most sensitive to inhibition by Tam was sterol Δ⁸-isomerase (Δ⁸-SI) (a 208-fold inhibition relative to lanosterol 14α-methyl demethylase), followed by sterol Δ²⁴-reductase (13-fold) and sterol Δ¹⁴-reductase (5.2-fold). The inhibition patterns of all four affected enzymes were found to be noncompetitive, despite widely different inhibition constants (K_i) of 0.21 to 23.5 μM. The inhibitory activity of Tam on Δ⁸-SI was not affected by detergent-mediated solubilization of the microsomes. In Chinese hamster ovary cells, inhibition of Δ⁸-SI activity (IC₅₀ = 0.15 μM) was paralleled by a decreased rate of [¹⁴C]-mevalonate incorporation into cholesterol (IC₅₀ = 0.70 μM). Our results should provide more insight into an underlying mechanism of Tam's cardioprotective role by interfering the operation of the pathway of cholesterol biosynthesis from lanosterol in mammals.