Tissue distribution

Early studies on P450 enzymes focused on the liver as the main drug-detoxifying organ and the adrenal gland for the metabolism of endogenous substrates, but it was soon recognized that other organs, notably those that serve as portals of entry to the body, such as the respiratory and the gastrointestinal tracts, also express P450s and other biotransformation enzymes. Each organ or tissue has its own profile of P450 enzymes that will determine the sensitivity of that tissue to a xenobiotic. It should be noted that most extrahepatic P450 enzymes are also present in the liver, often at a higher concentration, but can be regulated differently in different tissues, leading to altered xenobiotic exposures. Table 3 summarizes the tissue distribution of P450 enzymes that are commonly detected at either the mRNA (or, less commonly, the protein) level in various human organs.

Although P450 enzymes have been found in all tissues except skeletal muscles (Table 3) and red blood cells,17 the liver and intestine are organs of special significance with regard to drug metabolism. The liver is an impressive drug-metabolizing organ containing an abundance of P450s, UGTs, sulfotransferases (SULTs), and other drug-metabolizing enzymes. With regard to first-pass metabolism, P450s represent the most important hepatic enzymes.

Table 3 Tissue expression of cytochrome P450 enzymes involved in human drug metabolism

Tissue

Cytochrome P450 expression

Liver

1A1, 1A2, 2A6, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2S1, 3A4, 3A5, 3A7 (fetal), 3A43,

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