Adverse Drug Reactions due to Cytochrome P450 (Overview)
Dipl.-Biol. Birgit Busse
The enzymes of the cytochrome P450 superfamily play a major role in the metabolism of endogenous substrates, pollutants, carcinogenic substances as well as a number of drugs. The enzymes are mainly expressed in the liver and function as monooxygenases of the phase I reaction. Due to their homologies within their amino acid sequence, the superfamily of the cytochrom P450 genes is separated into 36 gene families and their subfamilies. The clinical significance and the association of genetic variants with altered enzyme activity of CYP2D6, CYP2C19 and CYP2C9 are well characterized within these subfamilies.
Changes in the enzymatic activities of phase I or phase II enzymes can be acquired (e.g. liver insufficiency) or inherited. Inherited factors are based on genetic variants that lead to a reduced or lacking enzyme activity, which results in slower metabolism of the substrates. On the other hand, there are variants that lead to an increased enzyme activity and therefore the substrates are metabolized more quickly (ultra-rapid metabolizer). The metabolizer phenotype has an impact on the efficacy of treatment and the tolerance of a drug.
CYP2D6 metabolizes approximately 20-30% of the most common drugs, including a large part of psychotropic and neuroleptic drugs as well as various cardiac agents or tamoxifen. For the CYP2D6 enzyme, both the poor metabolizer as well as the ultra-rapid metabolizer is described.
CYP2C19 metabolizes active agents such as proton pump inhibitors (PPIs), different psychotropic drugs or clopidogrel. Moreover, CYP2C19 often represents an alternative metabolic pathway for CYP2D6 substrates. For CYP2C19, both the poor metabolizer as well as the ultra-rapid metabolizer is described.
CYP2C9 is involved in the oxidative metabolism of non-steroidal antirheumatic drugs (such as diclofenac, ibuprofen), antidiabetics, phenytoin and coumarin derivatives. For CYP2C9, so far only the poor metabolizer is described.
CYP3A4 is involved in the oxidative metabolism of a variety of drugs, endogenous steroids and xenobiotics. For this enzyme inhibition or induction by various factors (e.g. diet, co-medication) has a much greater effect on enzyme activity than genetic disposition.
CYP1A2 is involved in the oxidative metabolism of a range of drugs and pollutants. The CYP1A2 enzyme is inducible by various substances (e.g. cigarette smoke). Genetic variants, however, are also associated with altered enzyme activity, but their clinical relevance has so far only partially been clarified. For this enzyme inhibition or induction by various factors (e.g. diet, co-medication) has a much greater effect on enzyme activity than genetic disposition.