Chaka C. Impraim

Usual human livers contain two major aldehyde dehydrogenase isozymes, cytosolic ALDH1 component and mitochondrial ALDH2 component, while human livers with "atypical" phenotype have only ALDH1 isozyme and are missing ALDH2 isozyme. Approximately 50% of orientals are atypical in respect to ALDH isozymes. We previously demonstrated an existence of enzymatically inactive but immunologically cross-reactive material (CRM) in atypical oriental livers. ALDH1 and ALDH2 isozymes were purified to homogeneity from usual livers, and ALDH1 and CRM were purified from atypical oriental livers. Amino acid compositions of ALDH1 and ALDH2 were similar to, but not identical with, each other. Amino acid compositions of ALDH2 and CRM were identical within analytical errors. Subunit molecular size of ALDH1 estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was 56,200 daltons, and that of ALDH2 was 52,600 daltons. The two isozymes did not contain a common subunit. Subunit molecular weight of CRM was identical with that of ALDH2. Double immunodiffusion precipitation revealed that ALDH1 and ALDH2 were immunologically analogous but not identical, and that CRM and ALDH2 were immunologically indistinguishable. These results support the genetic model that CRM is an abnormal defective protein resulting from a mutation of the ALDH2 locus.

1. The changes in membrane permeability to small molecules caused by Sendai virus [Pasternak & Micklem (1973) J. Membr. Biol. 14, 293-303] have been further characterized. The uptake of substances that are concentrated within cells is inhibited. Choline and 2-deoxyglucose, which become phosphorylated, and aminoisobutyrate and glycine, which are driven by a Na+-linked mechanism, are examples. The uptake of each compound under conditons where its diffusion across the plasma membrane is rate-limiting is stimulated by virus. Choline, 2-deoxyglucose and amino acids at high concentration, amino acids in Na+-free medium, and most substances at low temperature, are examples. It is concluded that virally mediated decrease of uptake is due to one of two causes. Substances that are accumulated by phosphorylation are not retained because of leakage of the phosphorylated metabolites out of cells. Substances that are accumulated by linkage to a Na+ gradient are no longer accumulated because of collapse of the gradient resulting from an increased permeability to Nat 2. Increased permeability to K+ and Na+ results in (a) membrane depolarization and (b) cell swelling. The latter event leads to haemolysis (for erythrocytes) and can lead to giant-cell (polykaryon) formation (for several cell types). 3. Recovery of cells can be temporarily achieved by the addition of Ca2+; permanent recovery requires incubation for some hours at 37 degrees C. 4. The possible significance of virally mediated permeability changes, with regard to clinical situations and to cell biology, is discussed.

Most Caucasians have two major liver aldehyde dehydrogenase isozymes, ALDH1 and ALDH2, while approximately 50% of Orientals have only ALDH1 isozyme, missing the ALDH2 isozyme. A remarkably higher frequency of acute alcohol intoxication among Orientals than among Caucasians could be related to the absence of the ALDH2 isozyme, which has a low apparent Km for acetaldehyde. Examination of liver extracts by two-dimensional crossed immunoelectrophoresis revealed that an atypical Japanese liver, which had no ALDH2 isozyme, contained an enzymatically inactive but immunologically cross-reactive material corresponding to ALDH2, beside the active ALDH1 isozyme. Therefore, the absence of ALDH2 isozyme in atypical Orientals is not due to regulatory mutation, gene deletion, or nonsense mutation, but must be due to a structural mutation in a gene for the ALDH2 locus, resulting in synthesis of enzymatically inactive abnormal protein.

More than 22 types of human papillomavirus (HPV) have been detected in genital tract squamous cell intraepithelial lesions. Seven of two hundred eighty-six (2.4%) genital tract tissues in which HPV DNA was detected by in situ hybridization contained two or more different HPV types. When analyzed by site, 5 of 204 (2.4%) of cervical intraepithelial lesions were infected by more than one type, compared with 2 of 82 (2.4%) of vulvar lesions. The rate for low-grade lesions was similar (5/218; 2.3%) to that for high-grade lesions (2/68; 2.9%). In contrast, two different HPV types were detected in 6/33 (18%) of tissues by the polymerase chain reaction (PCR) using type-specific primers for eight HPV types. It is concluded that infection by one HPV type is rarely associated with concurrent 'active' infection by a second HPV type, even though DNA of a different viral type can be detected by PCR in about one fifth of such cases. Further study is required to determine if an existing HPV infection can inhibit replication by a different HPV type.