Pathogenesis
Type II alveolar cells have many important functions in the lung, including the production of pulmonary surfactant, maintenance of fluid balance and composition in the airspace. Phospholipids that make up pulmonary surfactant are broken down by macrophages, releasing phosphate into the alveolar lining fluid. The loss of the Npt2b phosphate transported eliminates the ability of alveolar type II cells to pump phosphorus ions from the alveolar space back into the bloodstream, and leads to microlith formation.Epithelial deletion of Npt2b in mice results in an authentic mimic of the human condition, including accumulation of calcium phosphate microliths in the lung tissue and progressive diffuse radiographic opacities. The mouse model provides a useful platform for preclinical studies, including therapeutic trials of EDTA lavage and low phosphate diet/phosphate binders. Pathology
PAM may be confined to certain areas or show diffuse distribution through the lungs. Lung biopsy and autopsy specimens demonstrate characteristic intra-alveolar lamellar microliths. Calcium deposits in the alveoli begin in the lower lobes and spread over a period of years throughout the lungs. Diagnosis
PAM is usually diagnosed on the basis of a typical radiological pattern, namely a very fine, sand-like micronodulation of calcific density diffusely involving both lungs, with basal predominance. Many authors argue that this pattern precludes the need for a lung biopsy in most cases. After PAM is diagnosed in a given patient, family members should be screened by chest radiography, and parents should be counseled that future children are also at risk of developing the disease.
Finally an intramolecular attack from the hydroxyl group of C2 to the carboxylic acid group closes the ring and forms the lactone umbelliferone. Synthesis of methoxsalen
The biosynthetic route then continues with the activation of dimethylallyl pyrophosphate (DMAPP), produced via the mevalonate pathway, to form a carbo-cation via the cleavage of the diphosphates. Once activated, the enzyme umbelliferone 6-prenyltransferase catalyzes a C-alkylation between DMAPP and umbelliferone at the activated position ortho to the phenol, yielding demethylsuberosin. This is then followed by a hydroxylation catalyzed by the enzyme marmesin synthase to yield marmesin. Another hydroxylation is catalyzed by psoralen synthase to yield psoralen. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme xanthotoxol O-methyltransferase and S-adenosyl methionine to yield methoxsalen. Risks and side effects
Patients with high blood pressure or a history of liver problems are at risk for inflammation and irreparable damage to both liver and skin. The eyes must be protected from UVA radiation. Side effects include nausea, headaches, dizziness, and in rare cases insomnia. Methoxsalen has also been classified as an IARC Group 1 carcinogen (known to cause cancer) but is only cancerous when combined with light - UVA radiation. Society and culture
Author John Howard Griffin (1920–1980) used the chemical to darken his skin in order to investigate racial segregation in the American South. He wrote the book Black Like Me (1961) about his experiences. References
External links
"Methoxsalen". Drug Information Portal. U.S. National Library of Medicine.