Synthesis of the skeleton of the morphine molecule by mammalian liver

Abstract

The possibility that morphine could be synthesized in animals has long been considered¹ and a pathway in mammalian brain analogous to that in the opium poppy has been proposed². Substances have been detected in mammalian brain that are recognized by antisera raised against morphine^3–7. Recently we reported the presence of three such immunoreactive substances in bovine hypothalamus and adrenal, and in rat brain, and the definitive identification of two of them by gas chromatography-mass spec-trometry as morphine and codeine⁸. Incorporation of a labelled precursor has demonstrated the biosynthesis of morphine in the opium poppy from tyrosine-derived units⁹ (see Fig. 1). Intramolecular coupling of reticuline to form salutaridine is the critical step¹⁰ that generates the morphine skeleton (morphinan)¹¹ and the stereochemistry of the morphinan series⁹. We now report the conversion in vivo and in vitro of reticuline to salutaridine by rat liver, but this conversion is not detectable in rat brain and bovine adrenal. This is the first direct demonstration of the synthesis of a morphinan in an animal tissue and also supports the hypothesis that morphine and codeine in brain and adrenal are of endogenous origin.