A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Abstract

The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.

Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

“…The CYP super protein family has >300,000 members that are involved, among others, in the biosynthesis of steroids, fatty acids and natural products as well as in the degradation of drugs in humans and of xenobiotics in the environment. 41,42 Thus this is an important enzyme class with relevant applications in biocatalysis, biomedicine, pharmacology, toxicology and biotechnology [42][43][44] . Previously, we achieved the stereoselective and regioselective hydroxylation of testosterone (1) by evolving the self-sufficient Bacillus megaterium cytochrome P450 BM3 monooxygenase 40 .…”

A drug repositioning success: The repositioned therapeutic applications and mechanisms of action of thalidomide

“…39 High frequency of polymorphic P450 express in black led to high toxicity and unexpected drug interactions through drug metabolism. 15,39 It interacts with vincristine, platinum containing agents and bortezomib which can exacerbate its neurotoxicity. 40 Besides, it has also been documented to enhance the sedative effect of barbiturates, alcohol, chlorpromazine and reserpine.…”

“…Studies have shown that thalidomide can increase the production of oxygen free radicals and induce oxidative stress. 14,15…”

Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome

“…Medications administered concurrently that are substrates for the same cytochrome enzyme overwhelm the metabolic capacity of the cytochrome and interfere with efficacy or may result in toxicity [ 45 ]. If two drugs have the same affinity for an enzyme, they become competitive inhibitors in a dose related way [ 49 ]. If one of the drugs is a substrate for another cytochrome P450 enzyme with less affinity, metabolism may be shunted toward those less preferred pathways.…”