Hajime Oda

Cytochrome P450-dependent drug oxidation activities in liver microsomes of various animal species including rats, guinea pigs, dogs, monkeys, and humans

Abstract Levels of cytochrome P450 (P450 or CYP) proteins immunoreactive to antibodies raised against human CYP1A2, 2A6, 2C9, 2E1, and 3A4, monkey CYP2B17, and rat CYP2D1 were determined in liver microsomes of rats, guinea pigs, dogs, monkeys, and humans. We also examined several drug oxidation activities catalyzed by liver microsomes of these animal species using eleven P450 substrates such as phenacetin, coumarin, pentoxyresorufin, phenytoin, S-mephenytoin, bufuralol, aniline, benzphetamine, ethylmorphine, erythromycin, and nifedipine; the activities were compared with the levels of individual P450 enzymes. Monkey liver P450 proteins were found to have relatively similar immunochemical properties by immunoblotting analysis to the human enzymes, which belong to the same P450 gene families. Mean catalytic activities (on basis of mg microsomal protein) of P450-dependent drug oxidations with eleven substrates were higher in liver microsomes of monkeys than of humans, except that humans showed much higher activities for aniline p-hydroxylation than those catalyzed by monkeys. However, when the catalytic activities of liver microsomes of monkeys and humans were compared on the basis of nmol of P450, both species gave relatively similar rates towards the oxidation of phenacetin, coumarin, pentoxyresorufin, phenytoin, mephenytoin, benzphetamine, ethylmorphine, erythromycin, and nifedipine, while the aniline p-hydroxylation was higher and bufuralol 1′-hydroxylation was lower in humans than monkeys. On the other hand, the immunochemical properties of P450 proteins and the activities of P450-dependent drug oxidation reactions in dogs, guinea pigs, and rats were somewhat different from those of monkeys and humans; the differences in these animal species varied with the P450 enzymes examined and the substrates used. The results presented in this study provide useful information towards species-related differences in susceptibilities of various animal species regarding actions and toxicities of drugs and xenobiotic chemicals.

Association of active and passive smoking with allergic disorders in pregnant Japanese women: baseline data from the Osaka Maternal and Child Health Study

BACKGROUND Evidence remains inconclusive as to whether smoking is a risk factor for allergic disorders in adults. OBJECTIVE To investigate the relationship between active and passive smoking exposure and allergic disorders in pregnant Japanese women. METHODS This cross-sectional study included 1,002 pregnant women. Participants were classified as having asthma after the age of 18 years if they had used an asthma medication at any time after reaching the age of 18 years. Current atopic eczema and allergic rhinitis (including cedar pollinosis) were defined as being present if participants had received any drug treatment during the previous 12 months. Adjustment was made for age; gestation; parity; family history of asthma, atopic eczema, and allergic rhinitis; indoor domestic pets; family income; education; and the mite antigen level in house dust. RESULTS Current smoking, but not environmental tobacco smoke exposure, was independently related to an increased prevalence of asthma after the age of 18 years (adjusted odds ratio [OR], 2.66; 95% confidence interval [CI], 1.30-5.38). A significant positive association of current passive smoking exposure at home (adjusted OR, 1.89; 95% CI, 1.10-3.30) and at work (adjusted OR, 2.50; 95% CI, 1.29-4.76) with the prevalence of current allergic rhinitis was observed, whereas no measurable association with active smoking exposure was found. Neither active nor passive smoking was statistically significantly related to the prevalence of current atopic eczema. CONCLUSIONS These findings suggest that active smoking and environmental tobacco smoke exposure may increase the likelihood of asthma and allergic rhinitis, respectively, in pregnant Japanese women.

Relationships between Lifestyle-Related Factors and Immune Parameters in Middle-Aged Male Workers.

Relationships between Lifestyle‐Related Factors and Immune Parameters in Middle‐Aged Male Workers: Yumiko Nakano et al. Division of Industrial Health, Osaka Prefectural Institute of Public Health—Recent studies have demonstrated that unhealthy lifestyles and stress act as risk factors for various cardiovascular diseases, cerebrovascular disorders and cancer. The present study was carried out to investigate the effect of individual lifestyle and comprehensive lifestyle practices on T cell function in peripheral blood lymphocytes in 291 middle‐aged male workers belonged to 4 occupational groups: self employed men (I), employees of a television station (II), local civil servants (III) and workers in a manufacturing factory (IV). The proliferative responsiveness of the lymphocytes to phytohemagglutinin (PHA) was measured by the incorporation of radiolabeled thymidine by stimulated lymphocytes in vitro. lnterferonγ(IFNγ T helper type 1 cytokine) and interleukin‐4 (IL‐4; T helper type 2 cytokine) production from the stimulated lymphocytes were measured by quantitative sandwich enzyme immunoassay. Interviews by means of questionnaires including 19 items related to lifestyles, work stress, life event and health condition were performed. Subjects were classified into groups reporting healthy and unhealthy lifestyles according to their responses to the individual questionnaire. Then, the relationships between these lifestyle practices and the immune parameters were analyzed at the level of the occupational groups and the pooled subjects. The average number of unhealthy practices differed significantly among occupational groups, i.e., higher in the order of I, II, III and IV. Significantly negative correlations were observed between the number of unhealthy lifestyle practices and the PHA responses both at the level of the occupational groups and the pooled subjects. In contrast, there was no significant difference in IFN‐y production among occupational groups, though the group I showed a somewhat low tendency. The levels of IL‐4 in group I were noticeably higher than that in the other groups. It may be possible that severe suppression of cell‐mediated immunity changes the balance of T cell subsets from T helper type 1 to T helper type 2. For each lifestyle practice, subjects reporting “healthy” practices on 7 items showed significantly greater proliferative response to PHA than those reporting unhealthy practices. Subjects reporting “healthy” practices on two items showed significantly lower levels of IL‐4 compared with those reporting unhealthy practices. A 1.5‐yr follow up study performed in the subjects with low PHA responses showed that the reduction of unhealthy lifestyle practices significantly improved the PHA responses. Consequently, the present study suggests that the individual unhealthy lifestyle practices may act on the immune system cumulatively, and the measurement of PHA response may be used to evaluate the lifestyle practices of middle‐aged male workers at both the individual and the occupational group level.

Effects of Dioxin on Metabolism of Estrogens in Waste Incinerator Workers

The authors measured the concentrations of serum dioxins and urinary estrogen metabolites in 57 male waste incinerator workers to determine whether dioxin influenced the metabolism of estrogens. Concentrations of serum dioxin levels and urinary estrogen metabolites, such as estrone, 17α-estradiol, 2-hydroxyestrone, 2-methoxyestrone, 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestrone, 4-hydroxyestradiol, 4-methoxyestradiol, 16-hydroxyestrone, and estriol from the workers were measured. An analysis of covariance showed that mean estriol concentrations, adjusted for confounding factors among 3 serum dioxin levels, indicated a progressive increase with increasing serum dioxin level: 1.30, 1.41, and 2.02 nmol/mol creatinine at <30.3, 30.3-39.7, and >39.7 pg toxicity equivalent quantity/g lipid, respectively (F = 3.56, p = .036). This study showed that dioxin acts to metabolize estrogens to 16-hydroxyestrogens rather than to 2-or 4-hydroxyestrogens.