Adenylate cyclase is a key enzyme that couples with both the stimulatory and inhibitory G proteins (Gs and Gi). The cyclase has been purified and shown to be a glycoprotein of molecular weight 115, 000-180, 000. Cloning of cDNAs for adenylate cyclase showed that the cyclase is a member of a large family consisting of a variety of subtypes of the enzyme. These subtypes show different responses to calmodulin and G protein βγ subunits, and their distributions in tissues and organs are also different. This suggests that each subtype is involved in a particular physiological function. The general structure of adenylate cyclase is composed of two cytoplasmic domains and two membrane-spanning domains, each of which contains 6 transmembrane spans (12 spans in a molecule). The amino acid sequence of each cytoplasmic domain, which is thought to contain a nucleotide (ATP) binding site, is well-conserved among the various subtypes. This review also focuses on the regulation of adenylate cyclase activity by G protein subunits, particularly on several models for adenylate cyclase inhibition by Gi. As one of these mechanisms, direct inhibition of adenylate cyclase by the βγ subunits recently demonstrated by us will be discussed.
During the last decade, the influences of genetic factors on individual drug metabolizing capacity in humans have been characterized in fairly great detail at the molecular level. Debrisoquine/sparteine and mephenytoin polymorphisms are now known to be derived from defects in the human liver of specific forms of microsomal CYP (P450 or previously termed cytochrome P-450), CYP2D6 and CYP2C9 (2C18), respectively. In these polymorphisms, clear ethnic differences are observed in the incidence of poor metabolizers (PM). Although debrisoquine PM is detected in high incidence (5-10%) in Caucasians, little was found in Japanese. In contrast, mephenytoin PM is detected in higher percentages in Japanese (15-25%) than in Caucasians (3-7%). In this mini-review, current understanding of the molecular mechanism of both types of polymorphism and structural relationships of CYP2D6 and CYP2C9 substrates are shown. Relationships between specific phenotypes and cancer risks or disease are also discussed.
麻酔ラットを用いてrecombinant human superoxide dismutase(r-h-SOD)と再潅流性不整脈の用量反応関係を非可逆性再潅流性不整脈の発生率，すなわち，死亡率を指標に検討した．麻酔ラットの左冠動脈を4分間閉塞し，7分間再潅流した。r-h-SODは130～130,000U/kg/minで，また，化学的に不活性化したr-h-SOD(Apo-SOD)は10U/kg/minで，閉塞1分後から10分間静脈内へ投与した．虚血領域の大きさは全心臓重量に対する重量比(%)で表した．r-h-SODは死亡率を有意に抑制し，特に虚血領域の大きさが40～55%のとき，その抑制作用は検出され易く，430～130,000U/kg/minで有意であった．一方，Apo-SODは再潅流後の死亡率をまったく抑制しなかった．虚血により一過性の血圧低下，心拍数の上昇および不整脈の発生が認められた．しかし，これらの循環指標は，いずれの測定時点においても対照群とr-h-SOD群との間に有意な差はなく，r-h-SODの投与による影響は認められなかった．また，他の一連の実験で，r-h-SODを130～130,000U/kg/minで静脈内へ持続投与し，投与開始3分後に頚動脈から採血し，r-h-SODの濃度を測定した．r-h-SODの血漿中濃度は投与量に依存して上昇し，その値は8.5～6,600U/mlであった．以上のように，r-h-SODは虚血中の循環動態に影響せずに幅広い投与量で非可逆性再潅流性不整脈を抑制し，その時の有効血中濃度は28～6,600U/mlと推定された．