Lipoprotein(a) undergoes a dramatic, reversible conformational change on binding 6-amino-hexanoic acid (6-AHA), as measured by a decrease in the sedimentation rate, the magnitude of which is directly proportional to apo(a) mass. A similar reversible transition from a compact to an extended form has been shown to occur in plasminogen on occupation of a weak lysine binding site. The magnitude of the change in Lp(a) with large apo(a) is about 2.5 times that seen for plasminogen, however. Regardless of apo(a) size, binding analysis indicated that 1.4-4 molecules of 6-AHA bound per Lp(a) particle; the midpoint of the conformational change occurs at 6-AHA concentrations of 100-200 mM. Since rhesus Lp(a), which lacks both kringle V and the strong lysine binding site on kringle IV 10, also undergoes a similar conformational change, the phenomenon may be attributable to weak sites, possibly located in K-IV 5-8. Compact Lp(a), i.e., native Lp(a), had a frictional ratio (f/f0) of 1.2 that was independent of apo(a) mass, implying constant shape and hydration. For Lp(a) in saturating 6-AHA, f/f0 ranged from 1.5 to over 2.1 for the largest apo(a) with 32 K-IV, indicating a linear relationship between hydrodynamic volume and number of kringles, as expected for an extended conformation. However, only the variable portion of apo(a) represented by the K-IV 2 domains, participates in the conformational change; the invariant K-IV 3-9 domains remain close to the surface. These results suggest that apo(a) is maintained in a compact state through interactions between weak lysine binding sites and multiple lysines on apoB and/or apo(a), and that these interactions can be disrupted by 6-AHA, a lysine analog.

We determined the molecular weight of four different apo(a) polymorphs by sedimentation equilibrium in 6 M guanidine hydrochloride in order to estimate the molar ratio of apo(a) to apoB in Lp(a). They had molecular weights of 289,000, 310,000, 341,000, and 488,000 and 15, 16, 18, and 27 kringle 4 domains, respectively. Their carbohydrate content was similar (23.2 wt %), as was their partial specific volume (0.682 mL/g). Knowing the mass of apo(a), we estimated the molar ratio of apo(a) to apoB from (1) the molecular weight of the protein moiety of the four respective parent Lp(a) particles as calculated from their mass and percentage composition and the mass of apoB, (2) the mass of apo(a) lost from Lp(a) upon its reduction and carboxymethylation, by determining the difference in mass between Lp(a) and Lp(a-), and (3) from the mass (measured by sedimentation equilibrium in 6 M guanidine hydrochloride) of the lipid-free apoB-apo(a) complex (1.06 x 10(6) daltons) of the Lp(a) particle with the smallest apo(a) polymorph by subtracting the mass of apoB. Our results obtained with each of the three different physicochemical methods indicated that the protein moiety of each of the four Lp(a) particles that was investigated consisted of a complex of two molecules of apo(a) and one molecule of apoB.

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Photo-contact dermatitis (PCD) describes the adverse cutaneous reaction that occurs in some patients as a result of simultaneous exposure to a contactant and to light. PCD can be subdivided into photo-allergic and photo-irritant dermatitis depending on whether the contactant respectively invokes an allergic or irritant reaction. Photo-irritant reactions are commonly caused by plants, psoralens, and medications taken internally, whereas photo-allergic reactions are commonly caused by sunscreens and topical nonsteroidal anti-inflammatory medications. The work-up of photo-contact dermatitis includes a thorough history and physical exam augmented by patch and/or photopatch testing, as the cornerstone of treatment for PCD is identification and avoidance of the irritating or allergenic chemical. Photo-contact dermatitis has the potential to significantly impact quality of life, so an informed approach to diagnosis and management is critical. Clinical mimics of PCD include polymorphic light eruption, solar urticaria, actinic prurigo, hydroa vacciniforme, cutaneous porphyrias, and systemic disorders with photosensitivity such as lupus and dermatomyositis. Herein, we review the clinical presentation, differential diagnosis (including the clinical mimics mentioned above), pathogenic mechanisms, diagnostic testing, and therapeutic considerations for PCD.

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Although lipoprotein(a) (Lp[a]) has structural similarities to low-density lipoprotein (LDL) that include the presence of apolipoprotein Bioo, there is some disagreement over the strength of its interaction with the LDL receptor and its cellular catabolism by the LDL receptor-mediated pathway. To clarify this subject we evaluated LDL receptormediated binding and degradation of Lp(a) and LDL in three human cell lines. The binding of 50 nmol/L Lp(a) at 37°C to the LDL receptor of primary hepatocytes, macrophages, and fibroblasts was only 10%, 29%, and 29% of the respective value obtained with 50 nmol/L LDL. Analysis of 4°C binding curves indicated that Lp(a) and LDL had equal affinities for the LDL receptor of fibroblasts, whereas maximal binding of Lp(a) was remarkably lower than that of LDL. LDL receptormediated degradation of 50 nmol/L Lp(a) in hepatocytes, macrophages, and fibroblasts was only 17%, 22%, and 26%, respectively, of the value obtained with 50 nmol/L LDL and varied greatly among the cells in that it was lowest in hepatocytes, an order of magnitude greater in macrophages, and two S tudies on the cellular catabolism of lipoprotein(a) (Lp[a]) have focused on the role of the lowdensity lipoprotein (LDL) receptor because of its importance in the clearance of LDL from circulation and the fact that apolipoprotein (apo) B is an integral component of this LDL-like lipoprotein particle. Fibroblasts have been the cell line of choice in many of these investigations, 112 while other cell lines have received less attention.12 " 16 Because of the importance of the hepatic LDL receptor in the clearance of LDL, we examined Lp(a) catabolism in primary cultures of human hepatocytes. Recent advances in medium formulation, culture technique, and in understanding hepatotropic growth factors have made it possible to maintain human hepatocytes in culture with continued capacity for proliferation and survival for 2 months or longer. orders of magnitude greater in fibroblasts. In contrast, the nonspecific degradation rate of Lp(a) was similar to that of LDL in each of the three tested cell lines. However, the proportion of the degradation of Lp(a) that was nonspecific varied greatly, being 76%, 58%, and 33% in hepatocytes, macrophages, and fibroblasts, respectively. These studies indicate that not only is Lp(a) recognized by the LDL receptor but also that, in fibroblasts, Lp(a) and LDL have equal affinities for the LDL receptor, although Lp(a) has a much lower receptor occupancy than LDL. Additionally, they show that there are great cellular differences in the LDL receptormediated degradation of Lp(a). If these results can be extrapolated in vivo, where normal LDL levels are 40-to 50-fold higher than those of Lp(a), it would be unlikely that the hepatic LDL receptor is significantly involved in the degradation of Lp(a). (Arterioscler Thromb. 1994;14:770-779.) Key Words • dissociation constant • competitive inhibition • catabolism • steric hindrance tein with Hep G2 cells and with normal human hepatocytes.Drawing ...

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