Phase I reaction

Phase I reactions are typically divided into three categories oxidation, reduction, and 

Formally, oxidation involves the removal of electrons from a molecule. In a balanced reaction, an oxidation frequently has the net effect of removing hydrogen (H2) or hydride (H ) from a molecule. When a molecule or functional group is oxidized by a metabolic enzyme, the oxidation product tends to be more electrophilic and prone to attack by a nucleophile. In a biological system, water is omnipresent and serves as a common nucleophile. Therefore, oxidations are often coupled with a subsequent hydrolysis. These are technically separate steps but are commonly discussed together as one process. 

SCHEME 8.2 Different mechanisms for oxidative cleavage of alkyl groups 

Drugs that are administered in an inactive form and are metabolized to a structure with the desired biological activity are called prodrugs. Prodrugs are highlighted in the final section of this chapter. 

The last form of phase I metabolism is hydrolysis. Hydrolysis reactions generally involve acid derivatives. Specifically, esters and amides are hydrolyzed to carboxylic acids and an 

NADPH-P450 Reductase 1 NADPH-P450 Reductase  

The overall reaction occurs according to the equation as follows  

Among the reactions performed by the cytochrome P450 monooxygenase system, epox-idation, hydroxylation, N-dealkylation, O-dealkylation, desulfuration, and sulfoxidation are the most important with respect to pesticide metabolism  

In the fall army worm, Spodopterafrugiperda, sulfoxidation of phorate requires NADPH. It is inhibited by carbon monoxide and piperonyl butoxide, and induced by cytochrome P450 inducers (e.g., indole 3-carbinol and indole 3-acetonitrile) (Yu, 1985). 

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In general, phase I reactions, such as oxidation and ra-demethylation are delayed in the neonate but are fully operational at or above adult levels by 4-6 months of age in the full-term neonate [27a-30]. Conjugation pathways, such as glucuronidation, do not approach adult values until 3 or 4 years of age. Sulfation activity does appear to reach adult levels in early infancy. For drugs that are subject to metabolism by both pathways, such as acetaminophen, the efficient activity of the sulfation pathway allows infants and children to compensate for low glucuronidation ability... 

Beside the MMFO mediated (phase I) reactions there are a few other major reactions that are worthy of note. The two major ones involve ester hydrolysis and alcohol and aldehyde dehydrogenases. All mammalian species have an extensive ability to hydrolyze the ester bond. The products of the reactions then can go on to be further metabolized. In the pharmaceutical industry, this property has been utilized to synthesize prodrugs that is, chemicals that have desirable pharmaceutical properties (generally increased water solubility) that are not converted to their active moiety until hydrolyzed in the body. 

Phase I reactions (Figure 6.25) increase the polarity of the waste compound by oxidation or hydroxylation in a process which involves an electron transfer and... 

The CYP enzymes active in phase I reactions are often oxidases or hydroxylases, sometimes called mixed function oxidase (MFO). An oxidase enzyme introduces into the substrate (i.e. the unwanted compound) both atoms of an oxygen molecule whilst... 

Many of the specific enzymes involved with phase I reactions are subject to induction (see Section 3.3.3), that is increased synthesis by activation of the particular genes. Two clinical consequences arise from this ... 

In the liver s hepatocytes, the proportion represented by the sER is particularly high. It contains enzymes that catalyze so-called biotransformations. These are reactions in which apolar foreign substances, as well as endogenous substances—e. g., steroid hormones—are chemically altered in order to inactivate them and/or prepare them for conjugation with polar substances (phase I reactions see p. 316). Numerous cytochrome P450 enzymes are involved in these conversions (see p. 318) and can therefore be regarded as the major molecules of the sER. 

Phase i reactions (interconversion reactions). Type 1 reactions introduce functional groups into inert, apolar molecules or alter functional groups that are already present. In many cases, this is what first makes it possible for foreign substances to conjugate with polar molecules via phase 11 reactions (see below). Phase 1 reactions usually reduce the biological activity or toxicity of a substance ( detoxification ). However, some substances only become biologically active as a result of the interconversion reaction (see, for example, benzo[a]pyrene, p. 256) or become more toxic after interconversion than the initial substance ( toxification ). 

Phase II reactions (conjugate formation). Type II reactions couple their substrates (bilirubin, steroid hormones, drugs, and products of phase I reactions) via ester or amide bonds to highly polar negatively charged molecules. The enzymes involved are transferases, and their products are known as conjugates. 

The above classification of detoxication reactions has been developed for the metabolism of synthetic pesticides In plants. However, the same reactions can occur with natural exocons, such as allelopathic compounds, that have the same functional groups as synthetic pesticides. Most allelopathic chemicals contain functional groups that can be conjugated by Phase II reactions. Thus, detoxication of allelopathic compounds can be expected to proceed by conjugation with the omission of Phase I reactions. The remainder of this review will be concerned with the conjugation of allelopathic compounds. 

Does not go through phase I reactions good choice in the context of hepatic insufficiency... 

Metabolism and elimination are critical in determining medication blood level and longevity of action. Two main categories of metabolic reactions are phase I reactions and phase 11 reactions. Phase 1 reactions are oxidative reactions that involve the cytochrome P450 system, and phase 11 reactions are conjugative reactions. The rate-limiting step for most compounds occurs through phase I metabolism. 

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