1527
Carbocisteine sulphoxidation phenotype SIR,—The variable sulphoxidation of carbocisteine may reflect differences in the handling of endogenous substrates which have clinical implications. Indeed, an increased frequency of "poor sulphoxidisers" has been found in certain disease states, suggesting that this may be a factor in their aetiology. The status of the poor sulphoxidiser and the test protocol used have been questioned by Dr Kupfer and Professor Idle (May 5, p 1107). The discontinuity of carbocisteine sulphoxidation has been independently confirmed by Kupfer and Idle in unrelated laboratories using both the original analytical technique and a new chromatographic method. Their finding of 7/25 (28%) of a British population as poor sulphoxidisers (72% good sulphoxidisers) falls within the range previously cited for five healthy populations (278120%).1 In a large study in our laboratories the frequency of poor sulphoxiders was 138/409 (33-7%, 95% confidence interval 29-2—38 2%). A poor sulphoxidiser is at present defined as an individual who, after ingestion of 750 mg carbocisteine in the morning, excretes in the ensuing 0-8 h urine less than 14-3% of drug-related material as sulphoxide metabolites. This definition serves to divide the population but it implies nothing about mechanism(s), which remain to be investigated. Our 138 poor sulphoxidisers had 0-8 h drug recoveries ranging
profound
from 14-0% to 92-2%. We further studied 10 poor sulphoxidisers with 0-8 h recoveries below 50% and found that 8 excreted more drug-related sulphoxides after the first 8 h. If the definition of good/poor was redefined on the basis of 0-48 h urines these individuals became good sulphoxidisers. These findings accord with those of Kupfer and Idle. Clearly, the current protocol defines a heterogeneous group of poor sulphoxidisers comprising at least two subsets-"intrinsic poor" (high recovery poor) and "delayed excretors" (low recovery poor). In a clinical setting the current definition is useful provided matched controls are selected. Nevertheless, we should now be able to remove the potentially confusing subset of delayed excretors from the heterogeneous category of poor sulphoxidisers, and this may sharpen associations noted with clinical conditions and adverse drug reacúons.1,2 School of
Biochemistry, University of Birmingham, Birmingham B152TT, UK
R. H. WARING
Department of Pharmacology and Toxicology, St Mary’s Hospital Medical School, London W2
S. C. MITCHELL
1. Mitchell 2.
SC, Waring RH. The deficiency of sulfoxidation of S-carboxymethyl-Lcysteine. Pharmacol Ther 1989; 43: 237-49. Mitchell SC, Waring RH. S-Oxygenases III: human pharmacogenetics. In: Damani LA, ed. Sulphur-containing drugs and related organic compounds. vol IIA. Chichester: Ellis Horwood, Chichester, 1989: 101-19.
Simple non-radioactive method for detecting haemoglobin Constant Spring gene SIR,-Haemoglobin Constant Spring (HbCS) is characterised by a mutation in the a2-globin gene that produces an a-globin variant with 31 extra aminoacid residues. It is a major cause of HbH disease in South-East Asia.1 Because of its instability it cannot usually be detected by routine electrophoresis. We describe here a simple non-radioactive method based on the polymerase chain reaction (PCR) using allele specific primers2 to detect the HbCS
Agarose gel electrophoresis of amplified products
from three
individuals of different genotypes. DNA as size Lane M contains the Hincll fragments of phage
Carbocisteine sulphoxidation phenotype SIR,—The variable sulphoxidation of carbocisteine may reflect differences in the handling of endogenous substrates which have clinical implications. Indeed, an increased frequency of "poor sulphoxidisers" has been found in certain disease states, suggesting that this may be a factor in their aetiology. The status of the poor sulphoxidiser and the test protocol used have been questioned by Dr Kupfer and Professor Idle (May 5, p 1107). The discontinuity of carbocisteine sulphoxidation has been independently confirmed by Kupfer and Idle in unrelated laboratories using both the original analytical technique and a new chromatographic method. Their finding of 7/25 (28%) of a British population as poor sulphoxidisers (72% good sulphoxidisers) falls within the range previously cited for five healthy populations (278120%).1 In a large study in our laboratories the frequency of poor sulphoxiders was 138/409 (33-7%, 95% confidence interval 29-2—38 2%). A poor sulphoxidiser is at present defined as an individual who, after ingestion of 750 mg carbocisteine in the morning, excretes in the ensuing 0-8 h urine less than 14-3% of drug-related material as sulphoxide metabolites. This definition serves to divide the population but it implies nothing about mechanism(s), which remain to be investigated. Our 138 poor sulphoxidisers had 0-8 h drug recoveries ranging
profound
from 14-0% to 92-2%. We further studied 10 poor sulphoxidisers with 0-8 h recoveries below 50% and found that 8 excreted more drug-related sulphoxides after the first 8 h. If the definition of good/poor was redefined on the basis of 0-48 h urines these individuals became good sulphoxidisers. These findings accord with those of Kupfer and Idle. Clearly, the current protocol defines a heterogeneous group of poor sulphoxidisers comprising at least two subsets-"intrinsic poor" (high recovery poor) and "delayed excretors" (low recovery poor). In a clinical setting the current definition is useful provided matched controls are selected. Nevertheless, we should now be able to remove the potentially confusing subset of delayed excretors from the heterogeneous category of poor sulphoxidisers, and this may sharpen associations noted with clinical conditions and adverse drug reacúons.1,2 School of
Biochemistry, University of Birmingham, Birmingham B152TT, UK
R. H. WARING
Department of Pharmacology and Toxicology, St Mary’s Hospital Medical School, London W2
S. C. MITCHELL
1. Mitchell 2.
SC, Waring RH. The deficiency of sulfoxidation of S-carboxymethyl-Lcysteine. Pharmacol Ther 1989; 43: 237-49. Mitchell SC, Waring RH. S-Oxygenases III: human pharmacogenetics. In: Damani LA, ed. Sulphur-containing drugs and related organic compounds. vol IIA. Chichester: Ellis Horwood, Chichester, 1989: 101-19.
Simple non-radioactive method for detecting haemoglobin Constant Spring gene SIR,-Haemoglobin Constant Spring (HbCS) is characterised by a mutation in the a2-globin gene that produces an a-globin variant with 31 extra aminoacid residues. It is a major cause of HbH disease in South-East Asia.1 Because of its instability it cannot usually be detected by routine electrophoresis. We describe here a simple non-radioactive method based on the polymerase chain reaction (PCR) using allele specific primers2 to detect the HbCS
Agarose gel electrophoresis of amplified products
from three
individuals of different genotypes. DNA as size Lane M contains the Hincll fragments of phage
