Fig. 2

(A) Cell cycle-relevant, pro apoptotic long-chain C₁₆-ceramide [34] and very long-chain C_24:1-ceramide with sphingosine backbone and non-hydroxy fatty acid residue (ceramide fraction subclass NS representing 7% of cutaneous total ceramide [37]). A lack of very long-chain ceramides is responsible for loss of the barrier function of the stratum corneum [35, 38]. (B) Repercussions of lysosomotropic drugs and ceramide metabolism in keratinocytes. In standard conditions, ceramide de novo synthesis is localized in the endoplasmatic reticulum (ER) and ceramide degradation in lysosomes. Active pathways are marked with black arrows, and affected pathways are marked with arrows in shades of gray or red. Inhibition of acid sphingomyelinase (aSMase) and acid ceramidase (aCERase) is depending on the elevation of the lysosomal pH by the drug (strength of lysosomotropism and dosage). Enzymatic activity of aSMase and aCERase is strongly reduced, while residual activity remains for lysosomal phospholipase A₂ [39]. Very long-chain ceramides (e.g., C_24:1-ceramide) from the de novo synthesis at the ER accumulate in the cell membrane and the lysosomal synthesis of pro apoptotic long-chain C₁₆-ceramide is blocked [25]. In presence of pronounced NADPH (and NADH/ATP depletion), lysosomotropic compounds are unable to prevent the formation of C₁₆-ceramide and C₁₈-Ceramide, if stearic acid is present (see Fig. 3)