A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population.

Abstract

SUMMARY A population survey of 258 unrelated white British subjects showed a polymorphism for the 4-oxidation of debrisoquine. 'Extensive metabolisers' (EM) and 'poor metabolisers' (PM) are recognisable, 8.9% of the population being PM. Nine pedigrees ascertained through PM probands show that the PM phenotype is an autosomal Mendelian recessive character. The EM phenotype is dominant and the degree of dominance has been estimated at 30%. PM subjects are more prone to hypotension during debrisoquine therapy. The alleles controlling this polymorphism appear to control the oxidation of other drugs.The antihypertensive drug, debrisoquine, undergoes metabolic hydroxylation in man. The formation of the major metabolite, namely 4-hydroxydebrisoquine, displays polymorphism in the population.1 In this study, two well-resolved phenotypes were seen. The first was characterised by persons who 4-hydroxylated the majority of the drug and were thus designated extensive metabolisers (EM phenotype, about 95 % of the white British population). For these subjects, the metabolic ratio (MR), defined as % of dose as debrisoquine! % of dose as 4-hydroxy-debrisoquine excreted in the 0 to 8 hour urine, was of the range 0-01 to 9. In the second phenotype (poor metabolisers, PM, about 5% of British whites), MR values greater than 20 were observed, and thus these subjects had a relative inability to carry out debrisoquine 4-hydroxylation.The few families studied suggested strongly that PM subjects were autosomal recessives.In this paper, we describe a more extensive population study of white British subjects, together with further family data which uphold the resolution of the population into EM and PM phenotypes and confirm that the PM phenotype is an autosomal recessive trait.

Debrisoquine metabolism and genetic predisposition to lung cancer

“…We report a case-control study using the drug debrisoquine as a potential marker of such genetically determined susceptibility to lung cancer.Debrisoquine has only one major metabolite, 4-hydroxy debrisoquine (Idle et al, 1979), and the extent of 4-hydroxylation before excretion is controlled by a single gene and segregates into two distinct phenotypes -autosomal recessive poor metabolisers (about 9% of white populations, hydroxylating only 1-2% of a 10mg dose of debrisoquine) and homozygous and heterozygous dominant extensive metabolisers (hydroxylating 10-99%) (Evans et al, 1980;Steiner et al, 1985). Unchanged and 4-hydroxy debrisoquine can be measured easily and with high reproducibility (r=0.88) in urine (Evans et al, 1980 We recruited consecutive caucasian inpatients with newly diagnosed lung cancer from a London hospital.…”

“…Unchanged and 4-hydroxy debrisoquine can be measured easily and with high reproducibility (r=0.88) in urine (Evans et al, 1980 We recruited consecutive caucasian inpatients with newly diagnosed lung cancer from a London hospital. Cigarette smoking histories were documented as accurately as possible and recorded in pack-years (one-twentieth the average daily number of cigarettes smoked multiplied by the number of years of smoking).…”

Propafenone Poisoning—A Case Report with Plasma Propafenone Concentrations

“…There is the possibility that our patient had a CYP2D6 polymorphism resulting in a PM phenotype as an explanation for the undetectable 5-OHP. We postulate that this may have resulted in greater metabolism to the N-DPP metabolite; this is an active metabolite, but its relative potency and toxicity are poorly understood [7][8][9][10][11]. However, there are a number of limitations not least that this is a single case report, and we have been unable to measure the N-DPP metabolite.…”

“…As a result, up to 7% of the Caucasian population are poor metabolisers (PM) of propafenone [9,10]. Additionally, substantial dose-dependent metabolism of propafenone occurs in overdose; with higher concentrations of N-DPP than 5-OHP in the early stages of overdose, indicating a possible saturation of CYP2D6 metabolism to 5-OHP [11].…”

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

“…Thus, it was impossible to classify the patients as extensive or poor metabolizers according to hepatic hydroxylation velocity (15). Variable P450 cytochrome activity is known to occur naturally in humans and may be associated with differences in the pharmacokinetic profile of propranolol (16). Although the poor metabolizer phenotype is an autosomal Mendelian recessive character and the extensive metabolizer degree of dominance is estimated at 30% in the population, this selection bias was anticipated in the study design and paired statistical analysis was used to compare pharmacokinetics pre-and postoperatively.…”