Morphine metabolic pathways

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

When heroin is administered, it is rapidly converted to 6-monoacetylmorphine and then to morphine in the brain. Heroin is also more lipid soluble, suggesting that its increased potency is due to increased distribution into the brain. The major metabolic pathway for morphine is... 

The metabolism of morphine and related opiates has been investigated extensively and reviewed/424 426 It tends to be very rapid after parenteral administration but unpredictable after oral dosage. Scheme 2.26 illustrates the major metabolic pathways for morphine (1), codeine (2), and heroin (256). 

Codeine activation to morphine by demeth-ylation is controlled by the activity of the polymorphic cytochrome CYP2D6 (181). The clinical relevance of this observation derives from thefactthat about 10%of Caucasians lackthis metabolic pathway. Because poor metaboliz-ers cannot activate this widely used drug, for... 

The metabolic pathways in plants and living organisms were studied by means of tritium-labeled morphine (508, 509). The use of unnaturally tritium-labeled codeine derivatives showed that P. somniferum is able to... 

Several phase II enzymes may also be expressed as a function of age. Studies of paracetamol (acetaminophen) suggest that sulfation is the major metabolic pathway during the neonatal period and early infancy, changing to glucuronidation over several months (Miller et ai, 1976). The increase in morphine clearance due to glucuronidation is related to postconceptional age (Scott et ai, 1999). 

Genomic and transcriptomic technologies have been used to rapidly identify biosynthetic steps. There are currently over 40,000 expressed enzyme tags (ESTs) generated fi om alkaloid-producing plants that have been used to isolate genes involved in the alkaloid pathway [7]. Some alkaloid biosynthetic steps occur as spontaneous chemical reactions without the use of enzymes, for example, conversion of the intermediate neopine into codeinone in the morphine biosynthetic pathway. Also, some enzymes may catalyze two or more separate reactions in the pathway, for example, hyoscyamine 6-hydroxylase, which carries out two consecutive steps in the scopolamine biosynthetic pathway. Alkaloid biosynthesis also involves compartmentalization. Tissue-specific localization studies have shown that sequential biosynthetic enzymes can occur in distinct cell types [8, 9]. During the biosynthesis of the indole alkaloids vinblastine and vincristine in Catharanthus roseus, different enzymatic steps are carried out in different cellular compartments (Fig. 8.5) [10]. Various steps in the pathway are carried out in different types of cell. This requires the intercellular transport of metabolic intermediates. Similarly, scopolamine biosynthesis also involves two different cell types. 

Many functional groups undergo glucuronidation, but alcohols and phenols are the most common classes of compounds that undergo this metabolic pathway. For example, morphine, acetaminophen, and chloramphenicol are all metabolized via glucuronidation ... 

Why does morphine biosynthesis proceed through initial formation of (S)-reticuline as an intermediate, followed by epimerization, rather than through (J )-reticuline directly There is no obvious answer other than to say that many metabolic pathways contain such small inefficiencies, probably as a result of the evolutionary development of the responsible enzymes— what some people have called unintelligent design. ... 

Having discussed the biosynthesis of pyridoxal phosphate and morphine in the preceding two sections, we ll end this chapter on natural-products chemistry by going up yet one more level in complexity and looking at polyketide biosynthesis. Unlike what happens in many metabolic pathways, where each separate step is catalyzed by a separate, relatively small enzyme, erythromycin and other polyketides are assembled by a single massive enzyme called a synthase. The synthase contains many enzyme domains linked together, with each domain catalyzing a specific biosynthetic step in sequence. 

The existence of a different metabolic pathway for each unit became more evident when labeled dopamine (CLIII) was used as precursor of hydrastine. Only one unit was incorporated it formed the isoquinoline moiety of the alkaloid (225), a specific type of incorporation which was also found in the biosynthesis of morphine (226), chelidonine (227), and berberine (228) when the base was fed to the proper plants. Although dopamine has not been experimentally tested in the biogenesis of papaverine it is an acceptable hypothesis that it will be incorporated following the same pattern as with the other alkaloids. 

Heroin is rapidly metabolized to the active and specific metabolite 6-MAM and further to morphine and conjugated morphine. In turn, morphine is quickly converted to its principal metabolite M3G and, more slowly and in smaller amounts, to M6G. In general, the metabolism pathway of opiates is complex, because the taking place of several reactions of interconversion makes it difficult to certainly evaluate what a patient has consumed. For example, it is hard to understand if the patient, who has been prescribed diamorphine or morphine sulphate, has also consumed illicit heroin. The diagnosis cannot be done on the basis of morphine and 6-MAM contents, because their presence can be due to prescribed medications. Acetyl codeine would be a very useful marker for illicit heroin consumption, but unfortunately has a short half-life of only 237 min. Also through the determination of codeine and norcodeine, it is possible to evaluate whether the patient has taken illicit heroin as a source of morphine, but the interpretation is still difficult if codeine has been used in addition to diamorphine or illicit heroin. 

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