Clinical importance of non-genetic and genetic cytochrome P450 function tests in liver disease

Abstract

Liver disease is associated with reduced metabolic capacity for drugs that are metabolized by oxidative biotransformation. Three cytochrome P450 (P450 or CYP) gene families in liver microsomes (CYP 1, CYP2 and CYP3) appear to be responsible for much of the drug metabolism that takes place. The genetic polymorphism of the CYPs responsible for debrisoquine/ sparteine (CYP2D6) metabolism and S-mephenytoin (CYP2C19) metabolism has been well documented, but information on the impairment of each isoform in liver disease is still limited. There are two types of hepatic P450 function tests. One type consists of non-genetic P450 function tests (CYP1A2, 2A6, 2C9/10, 2E1 and 3A3/4), and probe drugs include caffeine, catalysed by CYP1A2, coumarin by CYP2A6, phenytoin by CYP2C6, chlorzoxazone by CYP2E1, and nifedipine, erythromycin and lidocaine by CYP3A3/4. The second type of genetic P450 function tests (CYP2C19 and CYP2D6) involves probe drugs such as S-mephenytoin, catalysed by CYP2C19, and debrisoquine and sparteine, catalysed by CYP2D6. The metabolism of the probe drugs used in non-genetic P450 function tests in patients with liver disease falls into two categories: reduced (CYP1A2, CYP2C, 2E1 and 3A) and unchanged (CYP2C). In genetic P450 function tests there seems to be a lesser degree of inhibition in poor metabolizers (PMs) than extensive metabolizers (EMs) among patients with liver disease. There have been very few reports on changes in metabolism of the probe drugs used in genetic P450 function tests in liver disease. In this paper the subject is reviewed.

Anestesia na população negra

“…The potential increase in paracetamol liver toxicity may be a consequence of poor metabolism (glucuronide binding, sulphatation) of paracetamol in blacks. The excretion of its mercaptopuric conjugate is higher among whites (9.3%) as compared to black population (4.2%) 71,77 . 4.…”

O Conhecimento de diferenças raciais pode evitar reações idiossincrásicas na anestesia?

“…O polimorfismo enzimático genético é um traço mendeliano na população em geral na forma de metabolizador lento (alelos mutantes) ou rápido. O importante sistema do citocromo P450 e as isoenzimas CYP geneticamente passíveis de polimorfismo (2C19, 2C9, 2D6, 1E2) fazem parte do metabolismo oxidativo (Fase I) dos xenobióti-cos e da maioria (70%) dos medicamentos da medicina atual e da moderna Anestesiologia [99][100][101][102] .…”

“…As 14 famílias e as 20 subfamílias das isoenzimas do Citocromo P450 constituem uma superfamília de hemoproteinas que catalisam o metabolismo oxidativo predominantemente hepático de xenobióticos (drogas anestésicas e adjuvantes, solventes, corantes e poluentes) e substâncias endógenas (esteróides, prostaglandinas, monoaminas e retinóides) no Homo sapiens há milhões de anos 89,[100][101][102] . As reações de epoxidação, N-dealquilação, O-dealquilação, S-oxidação e hidroxilação podem variar em função de dieta, jejum e uso concomitante de drogas que podem atuar como indutoras ou inibidoras enzimáticas.…”

“…Genetic enzyme polymorphism is a Mendelian trait in general population in the form of slow (mutant alleles) or fast metabolizers. The important cytochrome P450 system and isoenzymes CYP which are genetically prone to polymorphisms (2C19, 2C9, 2D6, 1E2), are part of xenobiotics and most (70%) current medical and anesthetic drugs oxidative metabolism (phase I) [99][100][101][102] .…”

“…The 14 families and 20 subfamilies of cytochrome P450 isoenzymes are a superfamily of hemoproteins which primarily catalyze liver oxidative metabolism of xenobiotics (anesthetic drugs and adjuvants, solvents, stains and pollutants) and endogenous substances (steroids, prostaglandins, monoamines and retinoids) in Homo sapiens for millions of years 89,[100][101][102] . Epoxydation, N-dealkylation, O-dealkylation, S-oxidation and hydroxylation reactions may vary as a function of diet, fast and concomitant use of enzyme inducing or inhibiting drugs.…”