Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the lactone umbelliferone. 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. 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. 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.