**2. Expression**

CYP1A1 and CYP1A2 belong to the CYP1 gene family; they are highly conserved and located on chromosome 15 [10,12]. CYP1A2 is constitutively expressed at high levels in human liver, whereas CYP1A1 was shown to be expressed at markedly lower levels in the organ but is also found in extrahepatic tissues including lung, intestine, prostate, kidney and placenta [11,13–19]. However, data on the protein abundance of hepatic CYP1A1 are conflicting; some studies demonstrated its absence in human liver, while others could clearly quantify the enzymatic protein [14,16,18,20–23]. In particular, recent mass spectrometry-based studies have demonstrated a substantial abundance of CYP1A1 in the human liver ranging from 0.5 to 9 pmol/mg microsomal protein [18,23].

In general, the available data on CYP1A1/2 expression are somewhat limited. There are sporadic studies on intestinal or hepatic CYP1A1 and/or CYP1A2 gene expression or protein abundance that are partly inconsistent and conflicting (Table 1). To overcome this limitation counteracting reliable conclusions, especially on the role of intestinal and hepatic CYP1A1, comprehensive information about gene and protein expression of CYP1A1 and CYP1A2 in intestinal and hepatic tissues from the same individuals are needed. So far, only one study from our group is available that included intestinal and hepatic tissue samples in parallel from organ donors, in order to overcome the known issue of high inter-subject variability in the expression of metabolizing enzymes [24]. However, this study only considered CYP1A2, but not CYP1A1.


**Table 1.** Overview of available data on mRNA expression and protein abundance of cytochrome P450 (CYP) 1A1 and CYP1A2 in the human intestine and liver (<sup>+</sup>, gene/protein expression was shown; -, not investigated n.d., not detectable; PTC, proteomics; WB, Western blot). Data are ranked in chronologicalorder(publicationdate).

Compared to CYP3A4 and CYP2C9, which are the most abundant intestinal CYP enzymes [16,24], CYP1A1 expression is rather little in the intestine and highly variable as well [16,30] (Figure 1). Paine et al. were able to detect CYP1A1 enzyme in only three of 31 investigated human jejunal samples at a range of 3.6 to 7.7 pmol/mg (Western blotting), while Miyauchi et al. using the targeted proteomics approach found CYP1A1 in 15 out of 28 analyzed human small intestinal samples (range: 0.07–2.3 pmol/mg) [16,30]. In parallel, also Shrivas et al. found CYP1A1 only in three out of 32 human liver microsomal samples using global proteomics [23]. Those findings indicate a substantial inter-subject variability in CYP1A1 protein that is most likely attributed to the individual lifestyle, including exposure to different diets or smoking, which were already shown to be important determinants of variability in the expression as well as the metabolic function of CYP1A enzymes [13,21,27,33]. In addition, experimental conditions may have partly contributed to the observed variability.

**Figure 1.** Comparative intestinal and hepatic gene expression and protein abundance of CYP1A1 and CYP1A2 (mean ± SD). Relative gene expression and absolute protein abundance of clinically relevant CYP450 enzymes in the human liver is presented in section (**A**,**B**) (data taken from Drozdzik et al. 2019 (**A**) and Achour et al. 2014 (**B**)). Sections C and D show relative gene expression and absolute protein abundance of clinically relevant CYP450 enzymes in the human small intestine observed in 30 ((**C**), own unpublished data) and 28 human jejunal tissue samples ((**D**), Miyauchi et al. 2016).

In contrast to the mentioned controversies on CYP1A1, CYP1A2 is doubtlessly expressed at considerable levels in the human liver, but not in the intestine (Table 1). A meta-analysis on the expression of 15 hepatic drug-metabolizing enzymes revealed that CYP1A2 contributes about 10% to all CYP enzymes [34]. After CYP3A4, CYP2E1, and CYP2C9, CYP1A2 showed the fourth highest protein abundance of all investigated hepatic CYP enzymes. These data have been confirmed by more recent mass spectrometry-based studies [24,31,35–37]. The mean hepatic microsomal protein abundance ranged from 14 to 35 pmol/mg, as determined by targeted proteomics [18,22,28,31,36,38]. Former data as derived from immunostaining studies determined considerably higher abundance, up to 65 pmol/mg [39,40], which might be interpreted with caution considering the issue of unspecific binding of antibodies. As a general feature of CYP1A1 and CYP1A2 expression, one must consider a substantial inter-subject variability, which seems to be caused by a complex interplay of genetic, epigenetics, and environmental factors [11,41].
