J. M. Ladero

CYP2D6 genes and risk of liver cancer

We have studied by use of PCR and XbaI and EcoRI restriction-fragment-length polymorphism whether mutations at the polymorphic CYP2D6 (debrisoquine hydroxylase) gene locus are associated with liver cancer. The frequency of CYP2D6 genes containing inactivating mutations was lower among 75 liver cancer patients than 200 healthy controls, and 40 cirrhotic subjects that did not develop liver cancer (frequency for carriers of two or more functional genes was 95% vs 74% vs 78%, respectively). Subjects who were homozygous for functional CYP2D6 genes appear to be at higher risk of developing primary liver cancer (odds ratio 6.40 [95% Cl] 2.4-17.5).

Oxidative polymorphism of debrisoquine in Parkinson's disease.

Oxidative phenotype and metabolic ratio (MR) of debrisoquine (DBQ) have been determined in 87 patients with Parkinsons disease and in 556 healthy control subjects. Three patients (3.45%) and 34 control subjects (6.12%), having an MR greater than 12.6, were classified as poor metabolisers (PM) of DBQ (ns). The distribution of MR values in the 84 Parkinsonian patients classified as extensive metabolisers (EM) showed a less efficient oxidative rate when compared with controls of the same phenotype (p less than 0.001). This difference may be due to enzymatic inhibition caused by drug treatment in 40 of these patients. As in patients not taking any drug known to inhibit the oxidation of DBQ, distribution of MR values was not different from that in controls. A negative correlation (r = -0.36, p less than 0.02) was found between MR of DBQ and age at onset of disease in patients free of drugs known to interact with DBQ metabolism. A higher rate of DBQ oxidation could be a genetic factor that delays the clinical onset of Parkinsons disease in predisposed people.

CYP2D6 genotypes in Spanish women with breast cancer

Wild type and three mutated alleles of the polymorphic CYP2D6 gene were studied in genomic DNA samples from 187 women with breast carcinoma and 151 healthy women by a mutation-specific polymerase chain reaction. The prevalence of the enzyme-inactivating CYP2D6(B) allele was higher among patients (18.2%) than in controls (11.6%; OR = 1.7; 95% c.i. = 1.14-3.13; P = 0.018). This excess was more marked in postmenopausal patients (19.8%, P = 0.0086) and in patients with non-ductal infiltrating carcinomas (25.8%, P = 0.003). The percentage of carriers of only one active gene (heterozygote extensive metabolizers) was higher in patients (31% vs. 19.9%; OR = 1.81; 95% c.i. = 1.06-3.11; P = 0.02). The CYP2D6(B)-carrier state may be related to a greater risk of breast cancer in women.

Polymorphic oxidation of debrisoquine in lung cancer patients

Oxidative polymorphism of debrisoquine (DBQ) was assessed in 84 patients (81 male) with histologically proven bronchogenic carcinoma and in 143 healthy male smokers. 80 (95%) patients and 133 (93%) controls, with a metabolic ratio (MR) below 12.6, were classified as extensive metabolisers of DBQ (no significant difference between patients and controls). Only 1 of the 73 patients with epidermoid or microcytic carcinomas was classified as a poor metaboliser (PM) (P = 0.031 compared with controls). 63 patients (75%) and 110 controls (77%) showed a very fast oxidative rate, with MR values under 1 (not significant). The EM phenotype of DBQ might be a secondary genetic risk factor for developing bronchogenic carcinoma in male smokers.

Acetylator polymorphism in Parkinson's disease.

SummaryAcetylator phenotype has been determined using sulphamethazine in 100 patients with Parkinsons disease and in 93 age-matched normal control subjects. Sixty-nine patients and 54 control subjects were classified as slow acetylators (NS). No relation was found among acetylator polymorphism and age at onset or clinical stage of disease.Amongst slow acetylators, the percentage of acetylated sulphamethazine in plasma was significantly lower in patients than in controls. Despite this finding, the results do not support any relationship between acetylator polymorphism and the risk of developing Parkinsons disease.

Acetylator polymorphism in rheumatoid arthritis.

SummaryAcetylator phenotype has been determined with sulphamethazine (sulphadimidine) in 69 Spanish patients with rheumatoid arthritis (48 females), all of whom were on second line therapy, and in 96 age-matched normal controls (54 females).Thirty-two patients (46.4%) and 56 controls (58.3%) were classified as slow acetylators. On analysing separately the females in both groups, 37.5% of patients and 63% of controls were found to be slow acetylators.No difference was found in the males (patients 66.3% and controls 52.4% slow acetylators).Rapid acetylator phenotype may be a risk factor for the development of severe rheumatoid arthritis in women.

Oxidative polymorphism of debrisoquine is not related to human colo-rectal cancer

SummaryThe oxidative polymorphism of debrisoquine (DBQ) has been determined in 89 patients with colo-rectal cancer and in 556 normal control subjects. Four patients and 34 controls, with a metabolic ratio >12.6, were classified as poor metabolisers of DBQ (n.s.).No difference was found in the distribution of the frequencies of the MR of DBQ between patients and controls.It is concluded that polymorphic oxidation of DBQ is not related to the risk of developing colo-rectal cancer in human beings.

Acetylator polymorphism in discoid lupus erythematosus.

SummaryAcetylator phenotype was determined, using sulphamethazine, in 37 patients with histologically confirmed discoid lupus erythematosus, who were free from visceral damage, and in 157 normal control subjects. Twenty patients (54%) and 90 control subjects (57.4%) were slow acetylators (p not significant). Acetylator polymorphism appears not to be related to the risk of developing pure cutaneous discoid lupus erythematosus.

Acetylator Phenotype in Psoriasis

Acetylator phenotype has been determined with sulfamethazine in 64 psoriatic patients and in 157 normal control subjects. Forty patients (62.5%) versus 90 control subjects (57.3%) were slow acetylators (p = NS). However, 81% of the 27 patients with psoriatic siblings were slow acetylators (p less than 0.05). Slow acetylator phenotype may be a genetic risk factor for the development of psoriasis.

RsaI Polymorphism at the CYP2E1 Locus and Risk of Primary Liver Cancer

Clinical Pharmacology & Therapeutics (1996) 59, 134–134; doi: 10.1038/sj.clpt.1996.36